TWI770552B - Quinazoline compounds - Google Patents

Abstract

Described herein are compounds of Formula (I) and tautomers and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.

Description

Quinazoline compounds

Described herein are compounds of formula (I) and tautomers and pharmaceutically acceptable salts thereof, compositions and formulations containing these compounds, and methods of using and making these compounds.

Despite advances in the treatment of HIV and AIDS, HIV infection remains a global health concern. As part of these treatments, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are often used, especially as a course of highly active antiretroviral therapy (HAART) therapy. a part. Although effective, there are disadvantages associated with the use of many known NNRTIs associated with HIV virus mutations that can lead to drug resistance. As such, there is still a need for further development of effective NNRTIs.

Described herein are the compounds of formula (I) and their pharmaceutically acceptable salts, compositions and formulations containing these compounds, or their pharmaceutically acceptable salts, and the use and manufacture of these compounds or their Methods of pharmaceutically acceptable salts.

In certain embodiments, the present disclosure relates to compounds of formula (I) or tautomers thereof,

或

；X¹、X²及X³係為各獨立的N或C(R¹¹)，但X¹、X²及X³中的最多2個為N；R¹係為-H、-CN、-OR^a、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R²係為-H、-CN、-OR^a、-NR^aR^b、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R³係為-H、-OR^a、-SR^a、-NR^aR^b、-NHC(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁴係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b、-OC(O)NR^aR^b、-CH₂C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁵係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b 、-OC(O)NR^aR^b、-CH₂C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁶係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b、-OC(O)NR^aR^b、-CH₂C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁷係為C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁸係為C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁹係為-H、C_1-6烷基或C_3-10環烷基，其中各C_1-6烷基及C_3-10環烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R¹⁰係為-H、C_1-6烷基或C_3-10環烷基，其中各C_1-6烷基及_C3-10環烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹¹係為獨立的-H、-CN、-OR^a、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其可為相同或不同的，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹²係為獨立的C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基、5-10元雜芳基、鹵素、OR^a、C(O)R^a、C(O)OR^a、 C(O)NR^aR^b、OC(O)NR^aR^b、NR^aC(O)OR^b、SR^a、S(O)_1-2R^a、S(O)₂F、S(O)₂NR^aR^b、NR^aS(O)₂R^b、N₃、CN或NO₂；其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基及5-10元雜環基以選自鹵素、OR^a、C(O)R^a、C(O)OR^a、C(O)NR^aR^b、OC(O)NR^aR^b、NR^aC(O)OR^b、SR^a-S(O)_1-2R^a、S(O)₂F、S(O)₂NR^aR^b、NR^aS(O)₂R^b、N₃、CN及NO₂基團的1、2、3、4或5個取代基任意地取代，且其可為相同或不同的；各R^a及R^b係為獨立的-H、-NH_2、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基或5-10元雜芳基，其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基及5-10元雜芳基被1、2、3、4或5個R¹³基團任意地取代，且其可為相同或不同的；或R^a及R^b與其附接的原子一起形成5-10元雜環基；以及各R¹³係為獨立的-CN、鹵素、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基或5-10元雜環基；或其互變異構物或其藥學上可接受之鹽類。 where Q is

or

; X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), but at most two of X ¹ , X ² and X ³ are N; R ¹ is -H, -CN, - OR ^a , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 ring Alkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ² is -H, -CN, -OR ^a , -NR ^a R ^b , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, and they may be the same or different; R ³ is -H, -OR ^a , -SR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁴ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C ( O) NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each of C _1-6 alkyl, C _3-10 cycloalkyl and C _{1- 6} heteroalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁵ is -H, -OR ^a , halogen, -NO ₂ , - CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C(O)NR ^a R ^b , C _1-6 alkyl, C _{3- 10} cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl is surrounded by 1, 2, 3, 4 or 5 R ¹² The groups are optionally substituted and may be the same or different; R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C(O)NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _{1 -6} alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁷ series is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein each C _1-6 alkyl, C _{3 -10} cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁸ is C _1-6 alkane group, C _3-10 cycloalkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein each of C _1-6 alkyl, C _3-10 cycloalkyl and C _{1 -6} heteroalkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁹ is -H, C _1-6 alkyl or C _{3- R _ _} ^{_ 10} is -H, C _1-6 alkyl or C _3-10 cycloalkyl, wherein each C _1-6 alkyl and _C3-10 cycloalkyl is replaced by 1, 2, 3, 4 or 5 R ¹² groups groups are optionally substituted, and they may be the same or different; each R ¹¹ is independently -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C _1-6 alkyl, C _{3 -10} cycloalkyl or C _1-6 heteroalkyl, which may be the same or different, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are separated by 1, 2 , 3, 4 or 5 R ¹² groups are optionally substituted, and they may be the same or different; each R ¹² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 Heteroalkyl, 5-10 membered heterocyclyl, _C6-10 membered aryl, 5-10 membered heteroaryl, halogen, OR ^a , C(O)R ^a , C(O)OR ^a , C(O) NR ^a R ^b , OC(O)NR ^a R ^b , NR ^a C(O)OR ^b , SR ^a , S(O) _1-2 R ^a , S(O) ₂ F , S(O) ₂ NR ^a R ^b , NR ^a S(O) ₂ R ^b , N ₃ , CN or NO ₂ ; wherein each of C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl and 5-10 membered Heterocyclyl is selected from halogen, OR ^a , C(O)R ^a , C(O)OR ^a , C(O)NR ^a R ^b , OC(O)NR ^a R ^b , NR ^a C(O)OR ^b , SR ^a -S(O) _1-2 R ^a , S(O) ₂ F, S(O) ₂ NR ^a R ^b , NR ^a S(O) ₂ R ^b , N ₃ , CN and NO ₂ groups 1, 2, 3, 4 or 5 substituents of the group are optionally substituted, and they may be the same or different; each R ^a and R ^b are independently -H, -NH _{2 ,} C _1-6 alkyl , C _3-10 Cycloalkyl, C _1-6 heteroalkyl, 5-10-membered heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl, wherein each C _1-6 alkyl, C _3-10 cycloalkane radicals, C _1-6 heteroalkyl, 5-10 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R ¹³ groups , and they may be the same or different; or R ^a and R ^b together with the atoms to which they are attached form a 5-10 membered heterocyclyl; and each R ¹³ is independently -CN, halogen, C _1-6 alkyl , C _3-10 cycloalkyl, C _1-6 heteroalkyl or 5-10 membered heterocyclyl; or a tautomer or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure pertains to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the present disclosure pertains to articles of manufacture comprising unit doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to a method of inhibiting reverse transcriptase in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to a method of treating or preventing HIV infection in a subject in need thereof, comprising adding a compound of formula (I) or a pharmaceutically acceptable thereof Salt is given to the subject.

In certain embodiments, the present disclosure relates to a method of preventing HIV infection in a subject comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, subjects are at risk of acquiring HIV, such subjects have one or more risk factors known to be associated with acquiring HIV.

In certain embodiments, the present disclosure relates to a method of treating or preventing HIV infection in a subject in need thereof, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more effective therapeutics amount of the other therapeutic agent is administered to the subject.

In certain embodiments, the present disclosure pertains to compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in medical therapy.

In certain embodiments, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HIV viral infection in a subject.

In certain embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

The remaining embodiments of the present disclosure are disclosed herein.

Figure 1 shows the results of the resistance profile of certain compounds to HIV-1 RT (Reverse Transcriptase) mutants.

Cross-references to related applications

This application claims priority to and benefits from US Application No. 62/096,748, filed on December 24, 2014, the disclosures of which are incorporated herein by reference in their entirety.

It is to be understood that the following description of the present disclosure is an example of what is claimed, and is not intended to limit the scope of the appended claims to the particular embodiments shown. The headings used throughout this disclosure are provided for convenience and should not be construed in any way to limit the scope of the claims. Embodiments described under any heading may be combined with embodiments described under any other heading.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant technical field. A dash before or after a chemical group is for convenience to indicate the point of attachment to the parent molecular group; the chemical group may be drawn with or without one or more dashes without losing its original meaning. The wavy line through the line in the chemical structure or the dashed line through the line in the chemical structure indicates the point of attachment of the group. Dashed lines in chemical structures represent arbitrary bonds. A prefix like "C _uv or (C _u -C _v )" indicates that the group following it has u to v carbon atoms. For example, "C _1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

When a tradename is used herein, it is intended to encompass the tradename product and the active pharmaceutical ingredient of the tradename product independently.

As used in this and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds and reference to "assay" includes reference to one or more assays, and the like.

As used herein, "alkyl" is a linear or branched monovalent hydrocarbon. For example, an alkyl group can have 1 to 20 carbon atoms (ie (C _{1 -20} )alkyl), or an alkyl group can have 1 to 10 carbon atoms (ie (C ₁ - ₁₀ )alkyl), or The alkyl group can have 1 to 8 carbon atoms (ie (C _{1 -8} )alkyl), or 1 to 6 carbon atoms (ie (C _{1 -6} )alkyl), or 1 to 4 carbon atoms (ie (C _{1-4 )} alkyl). Examples of alkyl groups include methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), 1-propyl ( n -Pr, n _{- propyl} , _{-CH2CH2CH3 )} , ₂ -propyl ( i -Pr, isopropyl, -CH( _CH3 ) ₂ ), 1-butyl ( n -Bu, n _- butyl, _{-CH2CH2CH2CH3} ), _{2 -} methyl- 1-propyl ( i -Bu, isobutyl, -CH2CH( _CH3 ) ₂ ), 2-butyl ( s -Bu, ₂ -butyl, -CH( _CH3 ) _{CH2CH3 )} , 2-methyl-2-propyl ( t -Bu, tert-butyl, _-C ( _CH3 ) ₃ ), ₁ -pentyl (n _- pentyl, _{-CH2CH2CH2CH2CH3 )} , 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH _{3 )} ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ) ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2- Hexyl (-CH( _CH3 ) _CH2CH2CH2CH3 ), ₃ -hexyl (-CH( _{CH2CH3 ) ( CH2CH2CH3 )} ), ₂ -methyl- ₂ -pentyl ( -C( _CH3 )2CH2CH2CH3), ₃ -methyl-2-pentyl (-CH( _CH3 ) _CH ( _{CH3 ) CH2CH3} ), ₄ -methyl- ₂ -pentyl group (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3- Amyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3 -Dimethyl-2-butyl (-CH( _CH3 )C( _CH3 ) ₃ and octyl (-( _CH2 ) _{7CH3 )} , but not limited thereto.

As used herein, "aryl" means a single all-carbon aromatic ring or a plurality of condensed all-carbocyclic ring systems in which at least one ring is aromatic. For example, in certain embodiments, aryl groups have 6 to 20 carbon ring atoms, 6 to 14 carbon ring atoms, or 6 to 12 carbon ring atoms. Aryl groups contain phenyl radicals. Aryl groups also include multiple condensed ring systems having about 9 to 20 carbon atoms (eg, ring systems comprising 2, 3, or 4 rings), wherein at least one ring is aromatic and the other rings may be aromatic or non-aromatic Sexual (ie carbocyclic compounds). These multiple condensed ring systems are optionally substituted with one or more (eg 1, 2 or 3) pendant oxy groups (oxo) on any carbocyclic moiety of the multiple condensed ring systems. The rings of multiple condensed ring systems may be connected to each other via fused, spiro bonds, and bridged bonds, as valency requirements permit. It is also understood that when reference is made to certain In the case of an aryl group that is a member of a subrange (eg, a 6-12 membered aryl group), the atomic range is all ring (ring) atoms of the aryl group. For example, a 6-membered aryl group can include phenyl and a 10-membered aryl group can include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

"Arylalkyl" means an alkyl radical as defined herein wherein one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl radical as described herein (ie, an aryl-alkyl molecular group) . The alkyl group of an aralkyl group contains an alkyl group of 1 to 6 carbon atoms (ie, an aryl(C ₁ -C ₆ )alkyl group). Aralkyl includes benzyl (benzyl), 2-phenylethan-1-yl (2-phenylethan-1-yl), 1-phenylpropan-1-yl (1-phenylpropan-1-yl), naphthyl methyl (naphthylmethyl), 2-naphthyleth-1-yl (2-naphthylethan-1-yl), etc., but not limited thereto.

"Boronic acid" means the -B(OH) ₂ group.

，其中各R可為相同或不同的。硼酸酯的例子包含硼酸頻哪醇酯(boronic acid pinacol ester)及硼酸兒茶酚酯(boronic acid catechol ester)。 "Boronic acid ester" means an ester derivative of a boronic acid compound. Suitable boronate ester derivatives comprise the formula -B(OR) ₂ , wherein each R system is independently an alkyl, aryl, aralkyl, heteroalkyl or heteroaryl group. In addition, the two Rs of -B(OR) ₂ can together form a cyclic ester, for example having the structure

, where each R can be the same or different. Examples of boronic acid esters include boronic acid pinacol ester and boronic acid catechol ester.

"Cycloalkyl" means a single saturated or partially unsaturated all-carbocycle (ie, C3- _C20 cycloalkyl) having ₃ to 20 carbon ring atoms, eg, 3 to 12 ring atoms, eg 3 to 10 ring atoms. The term "cycloalkyl" also refers to saturated and partially unsaturated multiple condensed fully carbocyclic ring systems (eg, ring systems comprising 2, 3 or 4 cyclic carbocycles). Thus, cycloalkyls contain polycyclic carbocyclic compounds such as bicyclic carbocyclic compounds (eg, bicyclic carbocyclic compounds having about 6 to 12 carbon ring atoms such as bicyclo[3.1.0]hexane (bicyclo[3.1. 0]hexane) and bicyclo[2.1.1]hexane (bicyclo[2.1.1]hexane) and polycyclic carbocyclic compounds (such as tricyclic and tetracyclic carbocyclic compounds with up to about 20 carbon ring atoms) ). The rings of a polycondensed ring system may be connected to each other via fused, spiro and bridged linkages, as valency requirements permit. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

"Halo or halogen" means fluoro, chloro, bromo and iodo.

When the term "heteroalkyl" is used herein, it means an alkyl group, as defined herein, wherein one or more carbon atoms of the alkyl group are substituted with O, S or ^NRq (or if the substituted carbon atom is terminal carbon is substituted with OH, SH or N(R ^q ) ₂ ), wherein each R ^q is independently H or (C ₁ -C ₆ )alkyl. For example, (C ₁ -C ₈ )heteroalkyl means a heteroalkyl group in which one or more carbon atoms of the C ₁ -C ₈ alkyl group is replaced by a heteroatom (eg O, S, ^NRq , OH, SH) or N( ^Rq ) ₂ ) substitution, which may be the same or different. Examples of heteroalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl, and N,N'-dimethylpropylamine. A heteroatom within a heteroalkyl group can be optionally oxidized or alkylated. The heteroatom can be located at any internal position of the heteroalkyl group or at the position of the group attached to the remainder of the molecule. Examples include _-CH2OCH3 , _-CH2CH2NHCH3 , _{-CH2CH2N ( CH3 ) -CH3} , _-CH2SCH2CH3 , _{-S ( O ) CH3} , _{-CH2CH 2} S(O) ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ , -CHCHN(CH ₃ )CH ₃ , -CH ₂ NHOCH ₃ and -CH ₂ OC(CH ₃ ) ₃ , but not limited thereto.

唑基(oxazolyl)或呋喃基(furyl)，但不限於此。此用語亦包含多縮合環系統(例如包含2、3或4環的環系統)，其中如前文定義的雜芳基基團可與選自雜芳基(以形成，例如像是1,8-

啶基之

啶基(naphthyridinyl))、雜環烷基(以形成，例如像是1,2,3,4-四氫-1,8-

啶基(1,2,3,4-tetrahydro-1,8-naphthyridinyl)之1,2,3,4-四氫

啶基(1,2,3,4-tetrahydronaphthyridinyl))、環烷基(以形成，例如5,6,7,8-四氫喹啉基(5,6,7,8-tetrahydroquinolyl))及芳基(以形成，例如吲唑基(indazolyl))的一個或多個環縮合以形成多縮合環系統。因此，雜芳基(單芳香環或多縮合環系統)具有約1至20個碳環原子及約1至6個雜原子。此等多縮合環系統的縮合環的碳環或雜環部分上可被一個或多個(例如1、2、3或4)側氧基任意取代。當價位要求允許時，可容許多縮合環系統的環經由稠合、螺接及橋接鍵結彼此連接。理解的是多縮合環系統的個別環能夠以任意順序相對於彼此連接。亦理解的是多縮合環系統(如前文對雜芳基的定義)的附接點為可為包含雜芳基、雜環、芳基的多縮合環系統的任意位置或多縮合環系統之碳環部分及包含碳原子及雜原子(例如氮)的多縮合環系統之任意合適原子。例示性的雜芳基包含吡啶基、吡咯基(pyrrolyl)、吡

基(pyrazinyl)、嘧啶基、嗒

基(pyridazinyl)、吡唑基(pyrazolyl)、噻吩基(thienyl)、引哚基(indolyl)、咪唑基(imidazolyl)、

唑基、噻唑基(thiazolyl)、呋喃基、

二唑基(oxadiazolyl)、噻二唑基(thiadiazolyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)、苯并噻唑基(benzothiazolyl)、苯并

唑基(benzoxazolyl)、吲唑基、喹噁基 (quinoxalyl)、喹唑啉基(quinazolyl)、5,6,7,8-四氫異喹啉基苯并呋喃基(5,6,7,8-tetrahydroisoquinolinyl benzofuranyl)、苯并咪唑基(benzimidazolyl)及噻萘基(thianaphthenyl)，但不限於此。 When used herein, the term "heteroaryl" means a single aromatic ring having at least one non-carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; this term also includes groups having at least one non-carbon atom in the ring. One such aromatic ring polycondensed ring system, the polycondensed ring system of which is further described below. Thus, this term includes a single aromatic ring having about 1 to 6 carbon ring atoms and about 1 to 4 heterocyclic atoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. Sulfur and nitrogen atoms can also exist in an oxidized state, making the ring aromatic. Such rings include pyridyl, pyrimidinyl,

oxazolyl or furyl, but not limited thereto. This term also includes polycondensed ring systems (eg, ring systems comprising 2, 3 or 4 rings), wherein a heteroaryl group as defined above may be combined with a group selected from heteroaryl (to form, for example, a 1,8-

of pyridyl

naphthyridinyl), heterocycloalkyl (to form, for example, 1,2,3,4-tetrahydro-1,8-

1,2,3,4-tetrahydro of pyridyl (1,2,3,4-tetrahydro-1,8-naphthyridinyl)

pyridyl (1,2,3,4-tetrahydronaphthyridinyl), cycloalkyl (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryl One or more rings of a radical (to form, for example, indazolyl) are condensed to form a polycondensed ring system. Thus, heteroaryl groups (monoaromatic or polycondensed ring systems) have about 1 to 20 carbon ring atoms and about 1 to 6 heteroatoms. The carbocyclic or heterocyclic moieties of the condensed rings of these polycondensed ring systems may be optionally substituted with one or more (eg 1, 2, 3 or 4) pendant oxy groups. When valency requirements permit, the rings of many condensed ring systems can be tolerated to be connected to each other via fused, spiro and bridged linkages. It is understood that the individual rings of the polycondensed ring system can be attached relative to each other in any order. It is also understood that the point of attachment of a polycondensed ring system (as defined above for heteroaryl) is any position that may be a polycondensed ring system comprising heteroaryl, heterocycle, aryl, or a carbon of the polycondensed ring system Ring moieties and any suitable atoms of polycondensed ring systems comprising carbon atoms and heteroatoms such as nitrogen. Exemplary heteroaryl groups include pyridyl, pyrrolyl, pyridyl

base (pyrazinyl), pyrimidinyl, da

pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,

azolyl, thiazolyl, furanyl,

oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoyl

benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl (5,6,7, 8-tetrahydroisoquinolinyl benzofuranyl), benzimidazolyl and thianaphthenyl, but not limited thereto.

(aziridine)、咪唑啶(imidazolidine)、亞胺基-側氧基咪唑啶(imino-oxoimidazolidine)、嗎福林(morpholine)、環氧乙烷(oxirane(epoxide))、氧環丁烷(oxetane)、哌

(piperazine)、哌啶(piperidine)、吡唑啶(pyrazolidine)、哌啶(piperidine)、吡咯啶(pyrrolidine)、吡咯啶酮(pyrrolidinone)、四氫呋喃(tetrahydrofuran)、四氫噻吩(tetrahydrothiophene)、二氫吡啶(dihydropyridine)、四氫吡啶(tetrahydropyridine)、

啶(quinuclidine)、N-溴吡咯啶(N-bromopyrrolidine)、N-氯哌啶(N-chloropiperidine)等，但不限於此。 When "heterocycloalkyl" or "heterocyclyl" is used herein, it means a single saturated or partially non-reactive group having at least one heteroatom (at least one heteroatom selected from oxygen, nitrogen or sulfur). Saturated non-aromatic ring or non-aromatic polycyclic ring system. Unless specifically stated otherwise, heterocycloalkyl groups have from 5 to about 20 ring atoms, such as 5 to 14 ring atoms, such as 5 to 10 ring atoms. Thus, the term includes single saturated or partially unsaturated rings having about 1 to 6 carbon ring atoms and 1 to 3 heterocyclic atoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring (eg, 3, 4, 5, 6 or 7 membered ring). This term also includes single saturated or partially unsaturated rings having about 4 to 9 carbon ring atoms and 1 to 3 heterocyclic atoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring (eg 5, 6, 7 , 8, 9 or 10 membered ring). When valency requirements permit, the rings of a polycondensed ring system can be connected to each other via fused, spiro and bridged linkages. Heterocycloalkyl contains nitrogen, azetidine, nitrogen

(aziridine), imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane , piper

(piperazine), piperidine (piperidine), pyrazolidine (pyrazolidine), piperidine (piperidine), pyrrolidine (pyrrolidine), pyrrolidinone (pyrrolidinone), tetrahydrofuran (tetrahydrofuran), tetrahydrothiophene (tetrahydrothiophene), dihydro Pyridine (dihydropyridine), tetrahydropyridine (tetrahydropyridine),

quinuclidine, N-bromopyrrolidine, N-chloropiperidine, etc., but not limited thereto.

"Hydroxy ((hydroxy) or (hydroxyl))" means an -OH group.

"Oxo" means a double bond oxygen (=O). In the compound in which the side oxygen group is bonded to the sp ² nitrogen atom, it is represented by nitrogen oxide ( N -oxide).

It is understood that combinations of chemical groups can be used or recognized by those of ordinary skill in the relevant art. For example, "hydroxyalkyl" can mean that a hydroxy group is attached to an alkyl group.

The term "optionally (optional) or (optionally)" means that the subsequent event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not.

亞胺-烯胺(imine-enamine)互變異構物：

內醯胺-內醯亞胺(lactam-lactim)互變異構物：

醯胺-亞胺酸(amide-imidic acid)互變異構物：

胺-亞胺(amino-imine)互變異構物：

；以及含有同時附接至環-NH-分子團及環=N-分子團之環原子的雜芳基的互變異構物形式，像是存在於吡唑(pyrazole)、咪唑(imidazole)、苯并咪唑(benzimidazole)、三唑(triazole)及四唑(tetrazole)中(請參見Smith,March's Advanced Organic Chemistry(5^th ed.),pp.1218-1223,Wiley-Interscience,2001；Katritzky A.and Elguero J,et al.,The Tautomerism of Heterocycles,Academic Press(1976))，但不限於此。 When used herein, "tautomers" means isomers of compounds that differ from each other in proton position and/or electron distribution. Thus, both proton transport tautomers and valence tautomers are expected and described with the understanding that more than two tautomers may exist for a given compound. Examples of tautomers include enol-keto tautomers:

Imine-enamine tautomers:

Lactam-lactim tautomers:

Amide-imidic acid tautomer:

Amine-imine tautomers:

; and tautomeric forms containing heteroaryl groups attached to both ring-NH- and ring=N-molecular ring atoms, such as those found in pyrazole, imidazole, benzene in benzimidazole, triazole and tetrazole (see Smith, March's Advanced Organic Chemistry (5 ^th ed.), pp. 1218-1223, Wiley-Interscience, 2001; Katritzky A. and Elguero J, et al., The Tautomerism of Heterocycles, Academic Press (1976)), but not limited thereto.

"Pharmaceutically acceptable" means compounds, salts, compositions, dosage forms and other materials useful in the preparation of pharmaceutical compositions suitable for use in veterinary or human pharmacy.

"Pharmaceutically acceptable salt" means a salt of a pharmaceutically acceptable compound that possesses (or is converted to possess) the desired pharmacological activity of the parent compound. These salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, benzenesulfonic acid, benzoic acid ( benzoic acid), camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid , lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid), oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid ( p-toluenesulfonic acid), trimethylacetic acid, etc. are formed, and when the acid protons present in the parent compound are either replaced by metal ions, such as alkali metal ions (such as sodium or potassium), alkaline earth metal ions (such as calcium or The salt formed when substituted by magnesium) or aluminum ions; or complexed with organic bases such as diethanolamine, triethanolamine, and N-methylglucamine. Also included as defined herein are ammonium and substituted or quaternized ammonium salts. A representative non-limiting list of pharmaceutically acceptable salts can be found in S.M.Berge et al., J.Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p.732, Table 38-5, both of which are incorporated herein by reference.

"(subject) and (subjects)" means humans, domestic animals (such as dogs and cats), agricultural animals (such as cattle, horses, sheep, goats and pigs), experimental animals (such as mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs and monkeys) and the like.

As used herein, "treatment or (treating)" refers to a means for obtaining a benefit or for a desired result. For the purposes of this disclosure, a benefit or a desired result includes, but is not limited to, alleviation of symptoms and/or reduction in severity of symptoms and/or prevention of worsening of symptoms associated with a disease or condition. In a certain embodiment, "treating" includes one or more of: a) inhibiting a disease or condition (eg, reducing one or more symptoms caused by a disease or condition, and/or reducing the extent of a disease or condition): b) delaying or arrest the development of one or more symptoms associated with the disease or condition (eg, stabilize the disease or condition, delay the progression or progression of the disease or condition); and c) alleviate the disease or condition, such as regression of clinical symptoms, amelioration of the condition, delay of the disease progress, improve quality of life and/or prolong survival.

As used herein, "delaying" the development of a disease or condition means to delay, hinder, delay, slow, stabilize and/or delay the development of the disease or condition. The delay can be of various lengths, depending on the course of the disease and/or the individual being treated. A sufficient or significant delay may actually encompass the prevention of not developing a disease or condition in an individual, as will be apparent to one of ordinary skill in the relevant art. For example, a method of "delaying" the progression of AIDS is to reduce the likelihood and/or reduce the extent of the disease for a given period of time compared to no method used. These comparisons can be based on clinical studies utilizing a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming an individual's HIV ⁺ status and estimating an individual's T cell count or other signs of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, High fever, swollen lymph nodes in the neck, armpit, or groin, or the presence of an opportunistic condition known to be associated with AIDS (eg, a condition that does not normally occur in individuals with a functioning immune system but occurs in AIDS patients). Development can also mean initially undetectable and includes occurrence, recurrence, and onset.

As used herein, "prevention or (preventing)" means a course of protection from the onset of a disease or disorder such that clinical symptoms of the disease do not develop. "Preventing" thus refers to administering a therapy (eg, administering a therapeutic substance) to a subject before a disease signal is detectable in the subject (eg, administering a therapeutic substance in the absence of a detectable infectious agent (eg, a virus) in the subject) object). A subject may be an individual at risk of developing a disease or disorder, such as an individual having one or more risk factors known to be associated with the development or onset of the disease or disorder. Thus, the phrase "preventing HIV infection" means administering an anti-HIV therapeutic substance to a subject who does not have detectable HIV infection. It is understood that the subject of anti-HIV preventive therapy may be an individual at risk of acquiring the HIV virus.

As used herein, an individual system "at risk" is an individual at risk of developing a condition requiring treatment. An "at risk" individual may or may not have a detectable disease or condition, and may or may not have developed a detectable disease prior to treatment with the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or condition and are known in the relevant art. Individuals with one or more of these risk factors have a higher likelihood of developing a disease or condition than individuals without these risk factors. For example, individuals with HIV are at risk of developing AIDS.

As used herein, the term "effective amount" means an amount effective to elicit a desired biological or medical response, which, when administered to a subject for the purpose of treating the disease, is sufficient to effect treatment of the disease. The effective amount will vary with the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. An effective amount can encompass a range of amounts. As understood in the relevant art, an effective amount can be one or more doses, meaning that a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. The effective amount can be given a One or more therapeutic agents, and administration of a single agent in an effective amount, concomitantly with one or more other agents, may or does achieve the desired or beneficial result. Appropriate doses of any co-administered compound may be arbitrarily reduced due to the combined effects (eg, additive or synergistic effects) of the compounds.

Unless otherwise expressly defined, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is expressly indicated (eg, where it is possible that two pairs of tautomers exist) Both tautomeric forms are anticipated and described below by representing one of the tautomeric forms). For example, if reference is made to a compound containing lactimide (eg, by structure or chemical name), it is to be understood that the present disclosure includes the corresponding lactimine tautomer and describes it as the same as lactimide are expressly recited alone or with lactamide. When more than two tautomers may exist, even if a single tautomeric form is described only by chemical name and/or structure, the present disclosure includes all such tautomers.

The compositions detailed herein may comprise racemic or non-racemic mixtures of stereoisomers of the compounds of the present disclosure or may comprise substantially pure isomers of the compounds of the present disclosure. Stereoisomers include mirror isomers and non-mirror isomers. If a compound possesses one or more asymmetrically substituted asymmetric centers or double bonds, it may exist in stereoisomeric forms and, therefore, can be produced as individual stereoisomers or as a mixture. Unless otherwise indicated, the description is intended to encompass individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the relevant art. (See Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992) It will be understood by those of ordinary skill in the relevant art that the present disclosure also includes any compound disclosed herein, which May be enriched in one or more isotopes above the naturally occurring ratios of any or all atomic isotopes, such as, but not limited to, deuterium ⁽ 2H or D).

It is also disclosed that 1 to n hydrogen atoms attached to carbon atoms in a compound can be deuterium Atom or D substitution, where n is the number of hydrogen atoms in the molecule. As known in the related art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. These compounds can increase resistance to metabolism and thus can usefully increase the half-life of the compounds when administered to mammals. See Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). These compounds are synthesized by means known in the relevant art, eg, using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Unless otherwise indicated, compounds of a given formula described herein encompass the disclosed compounds and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated compounds thereof type.

Depending on the specific substituents, compounds of formula I may exist in tautomeric forms. It is understood that two or more tautomers may exist for a given compound structure. For example, compounds of formula I (wherein ^R is -OH) may exist in at least the following tautomeric forms:

Various other tautomeric forms may exist and are intended to be encompassed by compounds of formula I, as understood by those of ordinary skill in the relevant art. Certain descriptions herein expressly refer to "their tautomers" with the understanding that even without this wording, the tautomers are still expected and described. Further, it is to be understood that the compounds of formula I can be converted between various tautomeric forms or exist in various ratios of each form depending on the particular environment of the compound.

The compounds disclosed herein may contain chiral centers, which may be in the (R) or (S) configuration, or may comprise mixtures thereof. Accordingly, the present disclosure includes stereoisomers of the compounds disclosed herein, which can be used alone or in admixture in any ratio. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Whether reacting starting materials for enantiomers, or separating isomers of the isomers of the present disclosure, such stereoisomers can be prepared or isolated using conventional techniques.

The compounds of the present disclosure may be compounds according to formula (I) with one or more opposite palm centers, which may be in the (R) or (S) configuration, or may comprise mixtures thereof.

The present disclosure includes both racemic mixtures of compounds of formula I and independent isomers of formula (I) or variants thereof. When more than one anti-palm centers are present in the compounds of the present disclosure, some, none, or all of the anti-palm centers may be enantiomer-enriched. Thus, a mixture of compounds of formula (I) may be racemic with respect to one or more opposite palm centers and/or enriched in enantiomers with respect to one or more opposite palm centers.

The present disclosure relates to compounds of formula (I),

或

； X¹、X²及X³係為各獨立的N或C(R¹¹)，但X¹、X²及X³中的最多2個為N；R¹係為-H、-CN、-OR^a、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R²係為-H、-CN、-OR^a、-NR^aR^b、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R³係為-H、-OR^a、-SR^a、-NR^aR^b、-NHC(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁴係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b、-OC(O)NR^aR^b、-CH₂C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁵係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b、-OC(O)NR^aR^b、-CH₂C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁶係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、-NHC(O)NR^aR^b、-OC(O)NR^aR^b、-CH₃C(O)NR^aR^b、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的； R⁷係為C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁸係為C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁹係為-H、C_1-6烷基或C_3-10環烷基，其中各C_1-6烷基及C_3-10環烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R¹⁰係為-H、C_1-6烷基或C_3-10環烷基，其中各C_1-6烷基及C_3-10環烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹¹係為獨立的-H、-CN、-OR^a、-C(O)OR^a、鹵素、C_1-6烷基、C_3-10環烷基或C_1-6雜烷基，其可為相同或不同的，其中各C_1-6烷基、C_3-10環烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹²係為獨立的C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基、5-10元雜芳基、鹵素、-OR^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-OC(O)NR^aR^b、-NR^aC(O)OR^b、-SR^a、-S(O)_1-2R^a、-S(O)₂F、-S(O)₂NR^aR^b、-NR^aS(O)₂R^b、-N₃、-CN或-NO₂；其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基及5-10元雜環基以選自鹵素、-OR^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-OC(O)NR^aR^b、-NR^aC(O)OR^b、-SR^a、-S(O)_1-2R^a、-S(O)₂F、-S(O)₂NR^aR^b、-NR^aS(O)₂R^b、-N₃、-CN及-NO₂基團的1、2、3、4或5個取代基任意地取代，且其可為相同或不同的； 各R^a及R^b係為獨立的-H、-NH_2、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基或5-10元雜芳基，其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基及5-10元雜芳基被1、2、3、4或5個R¹³基團任意地取代，且其可為相同或不同的；或R^a及R^b與其附接的原子一起形成5-10元雜環基；以及各R¹³係為獨立的-CN、鹵素、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基或5-10元雜環基；或其互變異構物或其藥學上可接受之鹽類。 where Q is

or

; X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), but at most two of X ¹ , X ² and X ³ are N; R ¹ is -H, -CN, - OR ^a , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 ring Alkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ² is -H, -CN, -OR ^a , -NR ^a R ^b , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, and they may be the same or different; R ³ is -H, -OR ^a , -SR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁴ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C ( O) NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each of C _1-6 alkyl, C _3-10 cycloalkyl and C _{1- 6} heteroalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁵ is -H, -OR ^a , halogen, -NO ₂ , - CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C(O)NR ^a R ^b , C _1-6 alkyl, C _{3- 10} cycloalkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl is surrounded by 1, 2, 3, 4 or 5 R ¹² The groups are optionally substituted and may be the same or different; R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₃ C(O)NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, wherein each C _{1 -6} alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁷ is C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein each of C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁸ is C _1-6 Alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein each of C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁹ is -H, C _1-6 alkyl or C _{3 -10} cycloalkyl, wherein each C _1-6 alkyl and C _3-10 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ¹⁰ is -H, C _1-6 alkyl or C _3-10 cycloalkyl, wherein each C _1-6 alkyl and C _3-10 cycloalkyl is surrounded by 1, 2, 3, 4 or 5 R The ¹² groups are optionally substituted, and they may be the same or different; each R ¹¹ is independently -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, which may be the same or different, wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl is surrounded by 1 , 2, 3, 4 or 5 R ¹² groups are optionally substituted, and they may be the same or different; each R ¹² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _{1 -6} heteroalkyl, 5-10 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O) _1-2 R ^a , -S(O ) ₂ F, -S(O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -N ₃ , -CN or -NO ₂ ; wherein each C _1-6 alkyl, C _3-10 Cycloalkyl, C _1-6 heteroalkyl and 5-10 membered heterocyclyl are selected from halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O) _1-2 R ^a , -S(O) ₂ F , -S( 1, 2, 3, 4 or 5 substituents of O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -N ₃ , -CN and -NO ₂ groups are optionally substituted, and may be the same or different; each of R ^a and R ^b is independently -H, -NH _{2 ,} C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, 5-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein each of C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, 5-10 membered heterocyclyl, C _6-10 aryl and 5- The 10-membered heteroaryl is optionally substituted with 1, ² , 3, 4 or ⁵ R groups, which may be the same or different; or R and R taken together with the atoms to which they are attached form ^a 5-10 membered Heterocyclyl; and each R ¹³ is independently -CN, halogen, C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, or 5-10 membered heterocyclyl; or Tautomers or pharmaceutically acceptable salts thereof.

In certain embodiments of formula (I), R ² is -H, -CN, -OR ^a or C _1-6 alkyl.

In certain embodiments of formula (I), R ² is -CN.

In one variation, the present disclosure relates to compounds of formula (II), which are compounds of formula (I):

或

；X¹、X²及X³係為各獨立的N或C(R¹¹)，但X¹、X²及X³中的最多2個為N； R¹係為-H、-CN、-OR^a、-C(O)OR^a、鹵素或C_1-6烷基，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R³係為-H、-OR^a、-NR^aR^b、-NHC(O)NR^aR^b、C_1-6烷基或C_1-6雜烷基，其中各C_1-6烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁴係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、C_1-6烷基或C_1-6雜烷基，其中各C_1-6烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁵係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、C_1-6烷基或C_1-6雜烷基，其中各C_1-6烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁶係為-H、-OR^a、鹵素、-NO₂、-CN、-NR^aR^b、C_1-6烷基或C_1-6雜烷基，其中各C_1-6烷基及C_1-6雜烷基被1、2、3、4或5個R¹²基團任意地取代，其可為相同或不同的；R⁷係為C_1-6烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁸係為C_1-6烷基、C_1-6雜烷基、鹵素、-OR^a、-CN或-NO₂，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R⁹係為-H或C_1-6烷基，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；R¹⁰係為-H或C_1-6烷基，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹¹係為獨立的-H、-CN、-OR^a、-C(O)OR^a、鹵素或C_1-6烷基，其 可為相同或不同的，其中C_1-6烷基被1、2、3、4或5個R¹²基團任意地取代，且其可為相同或不同的；各R¹²係為獨立的C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基、5-10元雜芳基、鹵素、-OR^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-OC(O)NR^aR^b、-NR^aC(O)OR^b、-SR^a、-S(O)_1-2R^a、-S(O)₂F、-S(O)₂NR^aR^b、-NR^aS(O)₂R^b、-N₃、-CN，或-NO₂；其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基及5-10元雜環基被選自鹵素、-OR^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-OC(O)NR^aR^b、-NR^aC(O)OR^b、-SR^a、-S(O)_1-2R^a、-S(O)₂F、-S(O)₂NR^aR^b、-NR^aS(O)₂R^b、-N₃、-CN及-NO₂基團的1、2、3、4或5個取代基任意地取代，且其可為相同或不同的；各R^a及R^b係為獨立的-H、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基或5-10元雜芳基，其中各C_1-6烷基、C_3-10環烷基、C_1-6雜烷基、5-10元雜環基、C_6-10芳基及5-10元雜芳基被1、2、3、4或5個R¹³基團任意地取代，且其可為相同或不同的；或R^a及R^b與其附接的原子一起形成5-10元雜環基；以及各R¹³係為獨立的-CN、鹵素、C_1-6烷基、C_3-10環烷基、C_1-6雜烷基或5-10元雜環基或其互變異構物或其藥學上可接受之鹽類。 where Q is

or

; X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), but at most two of X ¹ , X ² and X ³ are N; R ¹ is -H, -CN, - OR ^a , -C(O)OR ^a , halogen or C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, and which may be same or different; R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl are optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁴ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is replaced by 1 , 2, 3, 4 or 5 R ¹² groups are optionally substituted, and they may be the same or different; R ⁵ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is optionally replaced by 1, 2, 3, 4 or 5 R ¹² groups substituted, and they may be the same or different; R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkane group, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is optionally substituted by 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁷ is C _1-6 alkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein C _1-6 alkyl is arbitrarily selected by 1, 2, 3, 4 or 5 R ¹² groups substituted, and they may be the same or different; R ⁸ is C _1-6 alkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ , wherein C _1-6 alkane group is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ⁹ is -H or C _1-6 alkyl, wherein C _1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different; R ¹⁰ is -H or C _1-6 alkyl, wherein C _1-6 alkyl is 1, 2, 3, 4 or 5 R ¹² groups are optionally substituted, and they may be the same or different; each R ¹¹ is independently -H, -CN, -OR ^a , -C(O)OR ^a , halogen or C _1-6 alkyl, which may be the same or different, wherein the C _1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, and which may be the same or different; each R ¹² is independently C _1-6 alkyl, C _3-10 cycloalkyl, C _{1 -6} heteroalkyl, 5-10 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O) _1-2 R ^a , -S(O ) ₂ F, -S(O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -N ₃ , -CN, or -NO ₂ ; wherein each C _1-6 alkyl, C _{3- 10} cycloalkyl, C _1-6 heteroalkyl and 5-10 membered heterocyclyl are selected from halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O) NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O) _1-2 R ^a , -S(O) ₂ F , -S (O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -N ₃ , -CN, and 1, 2, 3, 4, or 5 substituents of the -NO ₂ groups are optionally substituted, and They may be the same or different; each R ^a and R ^b are independently -H, C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, 5-10 membered heterocycle base, C _6-10 aryl or 5-10 membered heteroaryl, wherein each C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, 5-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R ¹³ groups, and they may be the same or different; or R ^a and R ^b are attached thereto The attached atoms together form a 5-10 membered heterocyclyl; and each R ¹³ is independently -CN, halogen, C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, or 5 -10-membered heterocyclic group or its tautomer or its pharmaceutically acceptable salt.

。 In certain embodiments of formulae (I) and (II), Q is

.

。 In certain embodiments of formulae (I) and (II), Q is

.

In certain embodiments of formulae (I) and (II), X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), wherein two of X ¹ , X ² and X ³ which is N. In certain embodiments, X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), wherein one of X ¹ , X ² and X ³ is N. In certain embodiments, X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), wherein X ¹ , X ² and X ³ are not N.

In certain embodiments, in formulae (I) and (II), X ¹ , X ² and X ³ are each C(R ¹¹ ). In certain embodiments of formulae (I) and (II), X ¹ , X ² and X ³ are each CH. In certain embodiments, X ¹ is N; X ² is C(R ¹¹ ) and X ³ is C(R ¹¹ ). In certain embodiments, X ¹ is N; X ² is CH and X ³ is CH.

In formulae (I) and (II) in certain embodiments, X ¹ is N; X ² is N and X ³ is C(R ¹¹ ). In certain embodiments, X ¹ is N; X ² is C(R ¹¹ ) and X ³ is N. In certain embodiments, X ¹ is C(R ¹¹ ); X ² is N and X ³ is C(R ¹¹ ).

In certain embodiments of formulae (I) and (II), R ¹ is -H or C _1-6 alkyl. ^In certain embodiments, R1 is -H. In certain embodiments, R ¹ is C _1-6 alkyl. In certain embodiments, R ¹ is methyl.

In certain embodiments of formulas (I) and (II), X ¹ , X ² and X ³ are C(R ¹¹ ); each R ¹¹ is independently selected from -H, -CN, -OR ^a , halogen and C _1-6 alkyl; and R ¹ is selected from -H, -CN, -OR ^a , halogen and C _1-6 alkyl. In certain embodiments, X ¹ , X ² , and X ³ are C(R ¹¹ ); each R ¹¹ is -H; and R ¹ is -H.

In certain embodiments of formulae (I) and (II), X ¹ is N; X ² is C(R ¹¹ ) and X ³ is C(R ¹¹ ); each R ¹¹ is independently selected from— H, -CN, -OR ^a , halogen and C _1-6 alkyl; and R ¹ is selected from -H, -CN, -OR ^a , halogen and C _1-6 alkyl. In certain embodiments, X ¹ is N; X ² is C(R ¹¹ ) and X ³ is C(R ¹¹ ); each R ¹¹ is -H; and R ¹ is -H.

係選自

、

、

、

、

、

、

、

、

及

。 In certain embodiments of formula (I) and (II), the formula of formula (I) or (II)

selected from

,

,

,

,

,

,

,

,

and

.

為

或

。在某些實施例中，化學式(I)或(II)的化學式

為

。在某些實施例中，化學式(I)或(II)的化學式

為

。 In certain embodiments of formula (I) and (II), the formula of formula (I) or (II)

for

or

. In certain embodiments, the formula of formula (I) or (II)

for

. In certain embodiments, the formula of formula (I) or (II)

for

.

In certain embodiments of Formulas (I) and (II), R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkyl. In certain embodiments, R ³ is -H, -OR ^a , -NR ^a R ^b or -NHC(O)NR ^a R ^b .

In certain embodiments of formulae (I) and (II), R ³ is -NR ^a R ^b or -OR ^a . In certain embodiments, ^R3 is _-NH2 or -OH.

In certain embodiments, R ³ is -NR ^a R ^b . In certain embodiments, R ³ is -NR ^a R ^b , wherein each R ^a and R ^b are independently -H or C _1-6 alkyl, wherein C _1-6 alkyl is separated by 1, 2, 3 , 4 or 5 R ¹³ groups are optionally substituted. In certain embodiments, R ³ is -NR ^a R ^b , wherein each R ^a and R ^b are independently -H or C _1-6 alkyl. In certain embodiments, ^R3 is ^-NRaRb , wherein each ^Ra and ^Rb is independently ^-H , methyl, butyl, or cyclopropylmethyl. In certain embodiments, R ³ is -NH ₂ .

In formulae (I) and (II) in certain embodiments, R ³ is -OR ^a . In certain embodiments, ^R3 is -OH.

In certain embodiments of formulae (I) and (II), ^R3 is -H. In certain embodiments, R ³ is -NHC(O)NR ^a R ^b . In certain embodiments, R ³ is -NHC(O)NH ₂ .

In certain embodiments of formulae (I) and (II), R ⁴ is -H, -OR ^a , halogen, NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl. In certain embodiments, R ⁴ is -H or -OR ^a .

In certain embodiments of formulas (I) and (II), R ⁵ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl. In certain embodiments, R ⁵ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b or C _1-6 alkyl.

In certain embodiments of formulae (I) and (II), R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl. In certain embodiments of formulae (I) and (II), R ⁶ is -H.

In formulae (I) and (II) in certain embodiments, two of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, - OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl. In certain embodiments, both of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, -OR ^a , halogen, -NO ₂ , - NR ^a R ^b or C _1-6 alkyl. In certain embodiments, both of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, -OCH ₃ , halogen, -NO ₂ , - _NH2 or methyl.

In formulae (I) and (II) in certain embodiments, R ⁴ , R ⁵ and R ⁶ are -H.

In certain embodiments of formulae (I) and (II), R ⁷ is C _1-6 alkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ . In certain embodiments, R ⁷ is C _1-6 alkyl, halogen, or -OR ^a .

In certain embodiments of formulae (I) and (II), R ⁸ is C _1-6 alkyl, C _1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO ₂ . In certain embodiments, R ⁸ is C _1-6 alkyl, halo, or -OR ^a .

In formulae (I) and (II) in certain embodiments, R ⁷ and R ⁸ are the same and selected from C _1-6 alkyl, C _1-6 heteroalkyl, halogen, -OR ^a , - CN and -NO ₂ . In certain embodiments, R ⁷ and R ⁸ are the same and are selected from C _1-6 alkyl, halogen, or -OR ^a .

In formulae (I) and (II) in certain embodiments, R ⁷ and R ⁸ are C _1-6 alkyl. In certain embodiments, ^R7 and ^R8 are methyl.

In formulae (I) and (II) in certain embodiments, R ⁷ and R ⁸ are -OR ^a . In certain embodiments, R ⁷ and R ⁸ are -OCH ₃ .

In certain embodiments of formulae (I) and (II), R ⁷ and R ⁸ are halogen. In certain embodiments, R ⁷ and R ⁸ are fluoro.

In certain embodiments of formulae (I) and (II), R ⁹ is -H or C _1-6 alkyl. In certain embodiments, ^R9 is -H or methyl.

In certain embodiments of formulae (I) and (II), R ¹⁰ is -H or C _1-6 alkyl. In certain embodiments of formulae (I) and (II), R ¹⁰ is -H or methyl.

In certain embodiments of formulae (I) and (II), R ⁹ is -H or C _1-6 alkyl; and R ¹⁰ is -H or C _1-6 alkyl. In certain embodiments, R ⁹ is -H or methyl; and R ¹⁰ is -H or methyl. In formulae (I) and (II) in certain embodiments, R ⁹ and R ¹⁰ are -H.

、

、

及

。 In certain embodiments of formulae (I) and (II), Q is selected from

,

,

and

.

。 In certain embodiments of formulae (I) and (II), Q is

.

且R³為-NH₂。 在另一個變型中，Q為

且R³為-OH。 It is to be understood that any variation of Q of formulas (I) and (II) can be combined with any variation of ^R3 in formulas (I) and (II), such as listing each and every combination thereof specifically and individually. For example, in one variation of formulae (I) and (II), Q is

and R ³ is -NH ₂ . In another variation, Q is

and ^R3 is -OH.

It is to be understood that any variation of ^R7 of formulae (I) and (II) can be combined with any variation of ^R3 of formulae (I) and (II), such as listing each and every combination thereof specifically and individually . For example, in one variation of formulas (I) and (II), ^R7 is methyl and ^R3 is _-NH2 . In another variation, ^R7 is methyl and ^R3 is -OH.

It is to be understood that any variation of R in formulas (I) and (II) can be combined with any variation of ^R in ^formulas (I) and (II), such as listing each and every combination thereof specifically and individually . For example, in one variation of formulas (I) and (II), ^R8 is methyl and ^R3 is _-NH2 . In another variation, ^R8 is methyl and ^R3 is -OH.

It is to be understood that any variation of R4, ^R5 and ^R6 of formulas (I) and (II ⁾ can be combined with any variation of ^R3 in formulas (I) and (II), such as listed specifically and individually each and every combination. For example, in one variation of formulae (I) and (II), R ⁴ , R ⁵ and R ⁶ are each -H; and R ³ is -NH ₂ . ^In another variation, R4, ^R5 , and R6 are each -H ^; and ^R3 is -OH.

It is to be understood that any variation of X ¹ , X ² and X ³ of formulas (I) and (II) can be combined with any variation of R ³ in formulas (I) and (II), as listed specifically and individually each and every combination. For example, in one variation of formulae (I) and (II), X ¹ , X ² and X ³ are each CH; and R ³ is —NH ₂ . In ^one variation of formulae (I) and (II), X1 is N; X2 is ^CH and ^X3 is CH; and ^R3 is _-NH2 . ^In another variation, X1 is N; X2 is ^CH and ^X3 is CH; and ^R3 is -OH. ^In another variation, X1, X2, and ^X3 are each ^CH ; and ^R3 is -OH.

It is to be understood that any variation of R1 of formulas (I) and (II) can be combined with any variation of ^{R3 of} formulas (I) and (II), such as listing each and every combination thereof specifically and individually . For example, in ^one variation of formulas (I) and (II), R1 is hydrogen and ^R3 is _-NH2 . ^In another variation, R1 is hydrogen and ^R3 is -OH.

；以及e)R⁴、R⁵及R⁶各為-H。 In chemical formulae (I) and (II) in certain embodiments, when R ³ is -NH ₂ , the compound may have any one or more of the following structural features: a) X ¹ , X ² and X ³ are each CH ; b) R ⁷ is methyl; c) R ⁸ is methyl; d) Q is

and e) R ⁴ , R ⁵ and R ⁶ are each -H.

In a variant, the compound meets at least one of features (a) to (e). In another variation, the compound meets two or more (and in some variations, all) of features (a) through (e). In a specific variant, the compounds meet feature (a). In another variation, the compound meets features (a), (b) and (c). In another variation, the compound meets features (a) and (d). In another variation, the compound meets features (a) and (e).

；以及e)R⁴、R⁵及R⁶各為-H。 In chemical formulae (I) and (II) in certain embodiments, when R ³ is -OH, the compound may have any one or more of the following structural features: a) X ¹ is N; X ² is CH and X ³ is CH; b) R ⁷ is methyl; c) R ⁸ is methyl; d) Q is

and e) R ⁴ , R ⁵ and R ⁶ are each -H.

In a variant, the compound meets at least one of features (a) to (e). In another variation, the compound meets two or more (and in some variations, all) of features (a) through (e). In a specific variant, the compounds meet feature (a). In another variation, the compound meets features (a), (b) and (c). In another variation, the compound meets features (a) and (d). In another variation, the compound meets features (a) and (e).

時，化合物可具有以下結構特徵的任意一種或多種：a)X¹、X²及X³各為CH或X¹為N；X²為CH；以及X³為CH；b)R³為-NH₂或-OH；c)R⁷及R⁸為甲基；d)R⁴、R⁵及R⁶各為-H。 In certain embodiments of formulae (I) and (II), Q is

, the compound may have any one or more of the following structural features: a) X ¹ , X ² and X ³ are each CH or X ¹ is N; X ² is CH; and X ³ is CH; b) R ³ is - _NH2 or -OH; ^c ) ^R7 and ^R8 are methyl; ^d ) R4, ^R5 and R6 are each -H.

In a variant, the compound meets at least one of features (a) to (d). In another variation, the compound meets two or more (and in some variations, all) of features (a) through (d). In a specific variant, the compounds meet feature (a). In another variation, the compound meets features (a) and (b). In another variation, the compound meets features (a), (b) and (c). In another variation, the compound meets features (a), (b) and (d).

The present disclosure pertains to the following compounds or their pharmaceutically acceptable salts.

The present disclosure pertains to the following compounds or tautomers or pharmaceutically acceptable salts thereof:

，以及其互變異構物像是

。 The present disclosure relates to the following compounds or their pharmaceutically acceptable salts:

, and its tautomers like

.

pharmaceutical composition

Pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be prepared with conventional carriers (eg, inactive ingredients or excipient materials), which can be selected according to common practice. Tablets may contain excipients including glidants, fillers, binders and the like. Aqueous compositions can be prepared in a sterile manner, and generally can be isotonic when intended for delivery by means other than oral administration. All compositions may optionally contain excipients such as those listed in Rowe et al, Handbook of Pharmaceutical Excipients, 5 ^th edition, American Pharmacists Association, 1986. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. In certain embodiments, the compositions relate to solid dosage forms, including solid oral dosage forms. The pH of the composition may range from about 3 to about 11, but is generally about 7 to 10.

Although the active ingredient may be administered alone, it is preferred to present it in a pharmaceutical composition. Veterinary and human compositions comprise at least one compound of formula (I) together with one or more acceptable carriers and any other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and one other therapeutic ingredient. A carrier is "acceptable" in the sense that it is compatible with the other ingredients of the composition and is physiologically acceptable to the recipient. harmless.

Compositions include compositions suitable for various routes of administration, including oral administration. The compositions can be conveniently presented in unit dosage form and can be prepared by any method known in the relevant art of pharmacy. Such methods comprise steps associated with incorporating an active ingredient (eg, a compound of formula (I) or a pharmaceutical salt thereof) into one or more inactive ingredients (eg, carriers, pharmaceutical excipients, etc.). The compositions can be formulated by uniformly and intimately incorporating the active ingredient into liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, ^Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

The compositions described herein suitable for oral administration can be presented in discrete units (unit dosage forms) containing, but are not limited to, capsules, cachets, or tablets each containing a predetermined amount of the active ingredient.

The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients and any other therapeutic agents. The pharmaceutical composition containing the active ingredient can be in any form suitable for the intended method of administration. For example, for oral use, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral administration may be prepared according to any method known in the relevant art for the manufacture of pharmaceutical compositions, and such compositions may contain, in order to provide a palatable formulation, agents containing sweetening, flavoring, coloring and One or more agents of preservatives. It is acceptable in tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents such as calcium or magnesium carbonate, lactose, lactose monohydrate, croscarmellose sodium), povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as maize starch or alginic acid; binding agents such as cellulose, microcrystalline cellulose cellulose), starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques including microcoating to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long lasting effect. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be employed alone or with waxes.

The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form can vary with the subject intended to be treated and the particular mode of administration. For example, in certain embodiments, dosage forms for oral administration to humans may contain from about 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier materials such as inactive ingredients or excipient materials. In certain embodiments, the carrier material varies from about 5 to 95% (weight:weight) of the total composition.

It is to be understood that, in addition to the aforementioned ingredients specifically mentioned, the compositions of these examples may contain agents having conventional relevance for the type of compositions in question, for example compositions suitable for oral administration may contain flavour enhancements agent.

In certain embodiments, compositions comprising an active ingredient disclosed herein (a compound of formula (I) or a pharmaceutically acceptable salt thereof), in a variation, do not contain an agent that affects the efficiency with which the active ingredient is metabolized. Thus, it is to be understood that compositions comprising a compound of formula (I) in certain embodiments do not comprise, in certain embodiments, a compound that affects (eg, retards, hinders or slows down) the compound of formula (I) or is separate from the compound of formula (I), A medicinal agent for the metabolism of any other active ingredient administered consecutively or simultaneously. It is also to be understood that any of the methods, kits, articles of manufacture, etc. described herein, in certain embodiments, do not include compounds that would affect (eg, delay, hinder or slow) the compounds of formula (I) Or a metabolic agent of any other active ingredient administered separately, consecutively or simultaneously with the compound of formula (I).

Instructions

Disclosed herein are methods of inhibiting HIV reverse transcriptase in an individual in need thereof, comprising administering to the individual a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual in need is a human infected with HIV. In certain embodiments, the individual in need is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need is an individual at risk of developing AIDS. In certain embodiments, the individual in need is a human who has been infected with HIV and has developed AIDS. In certain embodiments of the methods disclosed herein, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual separately, in conjunction with, or concurrently with other active ingredients for the treatment of HIV, for the treatment of HIV Other active ingredients are HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase of reverse transcriptase), HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors , capsid polymerization inhibitors and other drugs for the treatment of HIV, and combinations thereof.

In certain embodiments, disclosed are methods of treating or preventing HIV viral infection in an individual (eg, a human) comprising administering to the individual a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, disclosed is the inhibition of HIV in an individual (eg, a human) A method of viral replication, treatment of AIDS, or delayed onset of AIDS, comprising administering to a subject any compound of formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, disclosed are methods of preventing HIV infection in an individual (eg, a human) comprising administering to the individual a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of acquiring HIV, such as an individual having one or more risk factors known to be associated with acquiring HIV.

In certain embodiments, disclosed are methods of treating HIV infection in an individual (eg, a human) comprising administering to the individual a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments, disclosed are methods of treating HIV infection in an individual (eg, a human) comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, concomitantly selected from the group consisting of HIV protease inhibitory compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for the treatment of HIV, and combinations thereof, are administered to a subject in a therapeutically effective amount of one or more other therapeutic agents.

In certain embodiments, disclosed is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for HIV infection (eg, HIV-1 or HIV virus (eg, a human) in an individual (eg, a human). , the replication of HIV-1) or the medical treatment of AIDS or delaying the onset of AIDS in an individual (eg, a human).

In certain embodiments, disclosed is the use of any compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV viral infection in an individual (eg, a human). Or HIV virus replication or AIDS or delayed AIDS onset. a real Examples relate to disclosing the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of HIV infection or AIDS, or for the therapeutic treatment of delaying the onset of AIDS.

In certain embodiments, disclosed is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for HIV infection in an individual (eg, a human). In certain embodiments, disclosed is the use of any compound of formula (I), or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of HIV infection.

In certain embodiments, in the methods of use, administration is to an individual (eg, a human) in need of treatment. In certain embodiments, in the method of use, administration is to an individual (eg, a human) at risk of developing AIDS.

Disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy. In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in a method of treating HIV viral infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (eg, a human). use.

Also disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a method of treating or preventing HIV in an individual in need thereof. In certain embodiments, the individual in need thereof is a human infected with HIV. In certain embodiments, the individual in need is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need is an individual at risk of developing AIDS. In certain embodiments, the individual in need is a human who has been infected with HIV and has developed AIDS.

Also disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the therapeutic management or delaying the onset of AIDS.

Also disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of HIV infection.

In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used as a research tool (eg, in a subject or in vitro to study inhibition of HIV reverse transcriptase).

way of giving

One or more compounds of formula (I) disclosed herein (also referred to herein as active ingredients) may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), dermal, vaginal, and injection (including subcutaneous, intramuscular, intravenous, intradermal, spinal and epidural), and the like. It will be appreciated that the preferred route will vary, eg, with the condition of the recipient. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

Dosing course

A compound, such as a compound of formula (I), can be administered to an individual for a desired period or period of time, such as at least about one month, at least about two months, at least about three months, at least about six months, according to an effective course of administration , at least about twelve months or more. In one variation, the compound is administered on a daily or intermittent schedule over the life of the subject.

The dose or frequency of administration of the compound of formula (I) can be adjusted during the course of treatment at the discretion of the administering physician.

The compounds can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once a day.

The compounds disclosed herein (eg, any of the compounds of formula (I)) can be administered in an effective dose of the compound of formula I. For example, a dose may be 10 mg to 1000 mg of compound, such as 75 mg to 100 mg of compound.

combination

In certain embodiments, disclosed are methods of treating or preventing HIV infection in a human having an infection or at risk of acquiring an infection, comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof class, and a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) other therapeutic agents is administered to a human. In a certain embodiment, disclosed is a method of treating HIV infection in a human having an infection or at risk of acquiring an infection, comprising combining a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with A therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) other therapeutic agents is administered to the human.

In certain embodiments, the present disclosure pertains to methods for treating HIV infection, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, concomitantly with a therapeutically effective amount of one or more of Other therapeutic agents suitable for the treatment of HIV infection are administered to patients in need.

Also disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and other active ingredients for the treatment of HIV, in a method of treating or preventing HIV. In certain embodiments, the other active ingredient for treating HIV is selected from the group consisting of HIV protease inhibitory compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotides of reverse transcriptase Inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and other drugs for the treatment of HIV, and the group consisting of combinations thereof.

Also disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in a method of treating or preventing HIV, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is Administer simultaneously, separately or sequentially with other active ingredients used to treat HIV. In certain embodiments, the other active ingredient for treating HIV is selected from HIV proteases Inhibitory compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibition agents, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for the treatment of HIV, as well as combinations thereof.

A compound disclosed herein (eg, any compound of formula (I)) can be combined with one or more other therapeutic agents (eg, 10 mg to 1000 mg of compound or 75 mg to 100 mg of compound) at any dose of compound of formula I.

In certain embodiments, disclosed are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, along with one or more (eg, one, two, three, one or both, or a to three) other therapeutic agents, and pharmaceutically acceptable carriers, diluents, or excipients.

In certain embodiments, disclosed are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, along with one or more (eg, one, two, three, one or both, or one to three) pharmaceutical compositions of other therapeutic agents.

In the above embodiments, the other therapeutic agent may be an anti-HIV agent. For example, in certain embodiments, the other therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase of reverse transcriptase), HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors (HIV non-catalytic site (or allosteric) integral inhibitors), HIV entry inhibitors (such as CCR5 inhibitors, gp41 inhibitors (such as fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibition agent, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (such as histone deacetylase inhibitors ( histone deacetylase inhibitors), proteasome inhibitors, protein kinase C (PKC) activators and BRD4 inhibitors), compounds that target the HIV capsid) ("capsid inhibitors", such as capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors), HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immunotherapies (e.g. Pd-1 modulators, Pd-L1 modulators, toll-like receptor modulators, IL-15 agonists ), HIV antibodies, double-specific antibodies and those containing HIV gp120 or gp41, combination drugs for HIV, HIV p17 matrix protein inhibitors, IL-13 antagonists, cis-peptidylproline Peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfide isomerase inhibitors, Complement C5a receptor antagonists, DNA formazan DNA methyl transferase inhibitor, HIV vif gene regulator, HIV-1 viral infectivity factor inhibitor, TAT protein inhibitor, HIV-1 Nef regulator, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors (mixed lineage kinase-3(MLK-3) inhibitors), Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain modulators containing protein 1 (COMM domain) containing protein 1 modulators), HIV Ribonuclease Hinhibitors, Retrocyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors ), HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors ), Cyclin dependent kinase inhibitors, Proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, anti- Reverse transcriptase priming complex inhibitors, PI3K inhibitors, disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/ 003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/00349 "antibody-like" therapeutic proteins of compounds of 8 (Gilead Sciences) and WO 2013/006792 (Pharma Resources) (eg DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), and other drugs for the treatment of HIV, and combinations thereof.

In certain embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors A group consisting of HIV non-catalytic site (or ectopic) integrase inhibitors, pharmacokinetic enhancers and combinations thereof.

In certain embodiments the compound of formula (I) is formulated into a tablet, which may optionally contain one or more compounds effective in the treatment of HIV. In certain embodiments, the tablet may contain other active ingredients for the treatment of HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleoside reverse transcriptase inhibitors Glycoside inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, these tablets are suitable for once-daily administration. In certain embodiments, the other therapeutic agents may be selected from one or more of: (1) a combination drug selected from ATRIPLA® (efavirenz) + tenofovir disoproxil fumarate disoproxil fumarate) + emtricitabine), COMPLERA® (EVIPLERA®, rilpivirine + tenofovir disoproxil fumarate + emtricitabine), STRIBILD® Elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine), dolutegravir + abacavir sulfate + Lamivudine, Dotegravir + Abacavir Sulfate + Lamivudine, Lamivudine + Nevirapine + Zidovudine, Dotegravir + Lipivirine, Sulfate atazanavir sulfate + cobicita, darunavir + cobicita, efavirenz + lamevudine + tenofovir disoproxil fumarate, hemifumar Tenofovir alafenamide hemifumarate + emtricitabine + cobicita + Tegvir, Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate + emtricitabine + cobicita, APH-0812, raltegravir ) + lamevudine, KALETRA® (ALUVIA®, lopinavir + ritonavir), antanavir sulfate + ritonavir, COMBIVIR® (chivudine + lamevudine) , AZT+3TC), EPZICOM® (Livexa®, Abacavir Sulfate + Lamevudine, ABC+3TC), TRIZIVIR® (Abacavir Sulfate + Chivudine + Lamevudine, ABC+AZT+3TC) , TRUVADA® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), tenofovir + lamevudine and lamevudine + tenofovir disoproxil fumarate A group consisting of; (2) HIV protease inhibitor selected from amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium , indinavir, indinavir sulfate, ropinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquiline Saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL- 100) and the group consisting of TMC-310911; (3) HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, selected from delavirdine, delavirdine mesylate , Virapine, etravirine, dapivirine, doravirine, lipivirine, efavirenz, KM-023, VM-1500, lentinan and AIC-292 Group; (4) HIV nucleoside or nucleotide inhibitor of reverse transcriptase, which is selected from VIDEX® and VIDEX® EC (didanosine, ddl), chiffudine, emtricitabine, Darnosin, stavudine, dideoxycytidine (zalcitabine), lamevudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alorofudine, phosphazid, fozivudine (fozivudine tidoxil), apricitabine, andoxovir, KP-1461, fosalvudine tidoxil, tenofovir, tenofovir disoproxil ( tenofovir disoproxil), tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide ), tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, antifovir two A group consisting of adefovir dipivoxil and festinavir; (5) HIV integrase inhibitor, which is selected from curcumin, derivatives of curcumin, chicoric acid, Derivatives of cichoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, rose Derivatives of red tricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tivostin, quercetin ), derivatives of quercetin, the group consisting of raltegravir, elvitegravir, dotegravir and cabotegravir; (6) HIV non-catalytic site or ectopic integrase inhibitor (NCINI) selected from Group consisting of CX-05168, CX-05045 and CX-14442; (7) HIV gp41 inhibitor selected from enfuvirtide, sifuvirtide and albuvirtide group; (8) HIV entry inhibitor selected from the group consisting of cenicriviroc; (9) HIV gp120 inhibitor selected from Rad ha-108(Receptol) and BMS- The group consisting of 663068; (10) a CCR5 inhibitor selected from the group consisting of aplaviroc, vicriviroc, maraviroc, sinevalo, PRO-140, Adaptavir ( Group consisting of RAP-101), TBR-220 (TAK-220) and vMIP (Haimipu); (11) CD4 attachment inhibitor selected from the group consisting of ibalizumab; (12) CXCR4 inhibition (13) a pharmacokinetic enhancer, selected from the group consisting of cobicistat and ritonavir; ( 14) Immunotherapy selected from dermaVir, interleukin-7, lexgenleucel-T (VRX-496), plaquenil (hydroxychloroquine), prune (proleukin) (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alfa, interferon gamma, hydroxyl Urea (hydroxyurea), mycophenolate mofetil (MPA) and its ester-derived mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL -2 XL, IL-12, polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, Tudor-like receptor modulators (tlr1, tlr2, tlr3, (15) HIV vaccine, which is selected from peptide vaccine, Recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccines), CD4-derived peptide vaccines, vaccine combinations, rgp120(AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E(gp120)(RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001(CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, multilayer DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine , AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV(FIT-06), AGS- 004, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA - Group consisting of CMDR and DNA-Ad5 gag/pol/nef/nev (HVTN505); (16) HIV antibodies, bispecific antibodies and "classes" comprising BMS-936559, TMB-360 and those against HIV gp120 or gp41 Antibodies "Therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives) selected from bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, KD-247, PGT145, PGT121, MDX010 (ipilimumab) ), VRC01, A32, 7B2, 10E8 and VRC07; (17) Latent reverser agents selected from histone deacetylase inhibitors, such as Romidepsin, vorinostat, panobinostat; proteasome inhibitors , like Velcade; and protein kinase C (PKC) activators like Indolactam, Prostratin, Ingenol B and DAG-lactone, ionomycin (Ionomycin), GSK-343, PMA, SAHA, BRD4 inhibitor, IL-15, JQ1, disulfram (disulfram) and amphotericin B (amphotericin B); (18) HIV nuclear sheath p7 ( (19) HIV maturation inhibitor, selected from the group consisting of BMS-955176 and GSK-2838232; (20) PI3K inhibition agent selected from idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib , rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, tarsilixib, XL-765, gedatolisib, VS-5584, copelisib ( copanlisib), CAI orotate, peliversin, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV- 1729, a group consisting of sonolisib, LY-3023414, SAR-260301 and CLR-1401; (21) disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2013/006792 ( Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012 Compounds of /003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and (22) other HIV-treating compounds A drug selected from the group consisting of TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, aloe polysaccharide (Acemannan), Gamimune, SCY -635, Prolastin, 1,5-Dicaffeic Acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR- 576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide and PA-1050040 (PA-040).

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more other therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two other therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three other therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four other therapeutic agents. one, two, three, four The one or more additional therapeutic agents may be different therapeutic agents selected from the same therapeutic agent type and/or different therapeutic agent types. In particular embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are conjugated to HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are conjugated to HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and HIV protease inhibitors Compound binding. In additional embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetics Enhancer binding. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is conjugated to two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

In particular embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with raltegravir, Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF+FTC), Maveroc, Envoviride, Epzicom® (Livexa®, Abacavir Sulfate + Lamevudine, ABC+3TC), Trizivir® (Abacavir Sulfate + Chivedine + Latin America) Vudine, ABC+AZT+3TC), Antifovir, Antifovir Disoproxil, Stribild ® (Evitegravir + Cobicita + Tenofovir Disoproxil Fumarate + Enn Tricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine + tenofovir disoproxil fumarate + emtricitabine) , Cobicita, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), antanavir, antanavir sulfate, dotegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir + ritonavir), ritonavir, emtricitabine, antanavir sulfate + ritonavir, Daru Navir, Lamevudine, Bolastine, Fosapenavir, Fosapenavir Calcium, Efavirenz, Combivir® (chivudine + lamevudine, AZT + 3TC), ezovirine, Fenavir, Fenavir mesylate, Interferon, Didanoxin, Stafodine, Indinavir, Indinavir sulfate, Tenofovir + Lamevudine, Chifedine, Vitamin Lapine, saquinavir, saquinavir mesylate, aldesleukin, dideoxycytidine, tipnavir, amperavir, deravidin, deravidine mesylate, Radha -108(Receptol), Hlviral, Lamevudine + Tenofovir Disoproxil Fumarate, Efavirenz + Lamevudine + Tenofovir Disoproxil Fumarate, Phosphine Azide, Lamev Dinolide + Virapine + Chifedine, Abacavir, Abacavir Sulfate, Tenofovir, Tenofovir Disoproxil, Tenofovir Disoproxil Fumarate, Tenofovir One, two, three, four or more other therapeutic agent combinations of alafenamide and tenofovir alafenamide hemifumarate.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir fumarate Disoproxil, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate were combined.

In particular embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil Nofovir alafenamide or tenofovir alafenamide hemi-fumarate conjugate.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a compound selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenol fumarate The first other therapeutic agent of the group consisting of fovir dipivoxil, tenofovir alafenamide and tenofovir alafenamide hemifumarate and selected from the group consisting of emtricitabine and lamevudine second of the group combination with other therapeutic agents.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a compound selected from the group consisting of tenofovir, tenofovir disoproxil, and tenofovir disoproxil fumarate The combination of the first other therapeutic agent and the second other therapeutic agent of the group consisting of tenofovir alafenamide and tenofovir alafenamide hemifumarate, wherein the second other therapeutic agent is emtricitabine .

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate amine or tenofovir alafenamide, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30 Or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or Tenofovir alafenamide, combined with 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or Tenofovir alafenamide, combined with 200 mg of emtricitabine. A compound disclosed herein (eg, a compound of formula (I)) can be combined with an agent disclosed herein in any dose of the compound (eg, 10 mg to 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound), as specifically and individually listed each dose combination.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate ester or tenofovir disoproxil, and 200 mg of emtricitabine combined. in some implementations For example, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 to 250; 200 to 300; 200 to 350; 250 to 350; 250 to 400; 350 to 400; of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or Tenofovir disoproxil, combined with 200 mg of emtricitabine. A compound disclosed herein (eg, a compound of formula (I)) can be combined with an agent disclosed herein in any dose of the compound (eg, 10 mg to 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound), as specifically and individually listed each dose combination.

In certain embodiments, when a compound disclosed herein is combined with one or more other therapeutic agents as described above, the components of the composition are administered in simultaneous or consecutive courses of treatment. When administered consecutively, the combination can be administered in two or more modes of administration.

In certain embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents for simultaneous administration to a patient in unit dosage form, eg, a solid dosage form for oral administration.

In certain embodiments, the compounds disclosed herein are administered concomitantly with one or more other therapeutic agents. Co-administration of the compounds disclosed herein with one or more other therapeutic agents generally means the simultaneous or sequential administration of the compounds disclosed herein and the one or more other therapeutic agents such that the treatment of the compounds disclosed herein and the one or more other therapeutic agents is effective The amounts may be present in the patient's body at the same time.

Co-administration of a unit dose comprising a compound disclosed herein precedes or follows administration of a unit dose of one or more other therapeutic agents, for example, within seconds, minutes, or hours of administration of one or more other therapeutic agents Compounds disclosed herein are administered. For example, in certain embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein within seconds or minutes. In certain embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents over a period of hours (eg, 1 to 12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein over a period of several hours (eg, 1 to 12 hours).

In certain embodiments, provided are methods of treating or preventing HIV infection in a human having an infection or at risk of acquiring an infection, comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof In this class, the human is administered concomitantly with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) other therapeutic agents. In a certain embodiment, provided is a method of treating HIV infection in a human having an infection or at risk of acquiring an infection, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, along with A therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) other therapeutic agents is administered to the human.

In certain embodiments, provided are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (eg, one, two, three, one or both, or one to three) other therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the present disclosure provides methods of treating HIV infection, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, concomitantly with a therapeutically effective amount of one or more suitable for treating HIV infection of other therapeutic agents are administered to patients in need.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more other therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two other therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three other therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four other therapeutic agents. One, two, three, four or more other therapeutic agents may be different therapeutic agents selected from the same therapeutic agent type and/or different therapeutic agent types.

How HIV combination therapy is administered

In certain embodiments, the compounds disclosed herein are administered with one or more other therapeutic agents. Co-administration of the compounds disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and the one or more other therapeutic agents, such that the treatment of the compounds disclosed herein and the one or more other therapeutic agents An effective amount may also be present in the patient's body. When administered consecutively, the combination can be administered in two or more modes of administration.

Co-administration of a unit dose comprising a compound disclosed herein precedes or follows administration of a unit dose of one or more other therapeutic agents, for example, within seconds, minutes, or hours of administration of one or more other therapeutic agents Compounds disclosed herein are administered. For example, in certain embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed by a period of several hours (eg, 1 to 12 hours) later A unit dose of one or more other therapeutic agents. In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein over a period of several hours (eg, 1 to 12 hours).

In certain embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents for simultaneous administration to a patient in unit dosage form, eg, a solid dosage form for oral administration.

In certain embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more compounds effective to treat HIV. In certain embodiments, the tablet may contain other active ingredients for the treatment of HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleoside reverse transcriptase inhibitors Glycoside inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, these tablets are suitable for once-daily administration.

HIV combination therapy

In the above embodiments, the other therapeutic agent may be an anti-HIV agent. For example, in certain embodiments, the other therapeutic agent is selected from combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latent reversers, targeting HIV capsid compounds, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL -13 antagonists, peptidyl proline cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonism Antibiotics, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing Inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1-containing COMM domain modulators, HIV RNase H inhibitors, retrocyclin modulators, CDK-9 inhibitors , dendritic ICAM-3 snapping non-integrin 1 inhibitor, HIV GAG protein inhibitor, HIV POL protein inhibitor, complement factor H modulator, ubiquitin ligase inhibitor, deoxycytidine kinase inhibitor, cycle Protein-dependent kinase inhibitor, proprotein convertase PC9 stimulator, ATP-dependent RNA helicase DDX3X inhibitor, reverse transcriptase-induced complex inhibitor, G6PD and NADH-oxidase inhibitor, pharmacokinetic enhancer , HIV gene therapy, HIV vaccine and combinations thereof.

HIV combination drugs

Examples of combination drugs include ATRIPLA ^® (efavirenz, tenofovir disoproxil fumarate and emtricitabine); COMPLERA ^® (EVIPLERA ^® ; ripivillin, tenofovir disoproxil fumarate furate and emtricitabine); STRIBILD ^® (elvitegravir, cobicita, tenofovir disoproxil fumarate and emtricitabine); TRUVADA ^® (tenofovir fumarate Dipyridoxate and emtricitabine; TDF+FTC); darunavir, tenofovir alafenamide hemifumarate, emtricitabine and cobicitabine; efavirenz, lamevudine and tenofovir disoproxil fumarate; lamevudine and tenofovir disoproxil fumarate; tenofovir and lamevudine; tenofovir alafenamide and emtricita Bing; tenofovir alafenamide, emtricitabine, and lipivirin; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate amines, emtricitabine, and lipivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicita, and elvitegravir; COMBIVIR ^® (chifeudine and lamevudine) ; AZT+3TC); EPZICOM ^® (LIVEXA ^® ; abacavir sulfate and lamevudine; ABC+3TC); KALETRA ^® (ALUVIA ^® ; lopinavir and ritonavir); TRIUMEQ ^® (dortegra Abacavir, Abacavir, and Lamevudine); TRIZIVIR ^® (Abacavir, Chivudine, and Lamevudine Sulfates; ABC+AZT+3TC); Antanavir and Cobicita; Antanavir Sulfate Vibril and Cobicita; Antanavir Sulfate and Redonavir; Darunavir and Cobicita; Dotegravir and Ripivirine; Dotegravir and Ripivirine Hydrochloride ; dotegravir, abacavir sulfate, and lamevudine; lamevudine, vilapine, and chivudine; raltegravir and lamevudine; doravirine, lamevudine, and tenofovir fumarate pyrifurate; doravirine, lamevudine, and tenofovir disoproxil; ropinavir, ritonavir, chivudine, and lamevudine; Vacc-4x and romidepsin; and APH-0812 .

other HIV medicines

Examples of other drugs used to treat HIV include aloe vera, aliprevir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, plastine, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF Gene Therapy, BlockAide, ABX-464, AG-1105, BIT-225, CYT-107, HGTV-43, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV -205, PA-1050040 (PA-040), PGC-007, SCY-635, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

HIV protease inhibitor

Examples of HIV protease inhibitors include amperavir, antanavir, bucanavir, darunavir, frasapenavir, fosapenavir calcium, indinavir, indinavir Wei, lopinavir, fenavir, fenavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipunavir, DG-17, TMB-657 (PPL-100), T-169 and TMC-310911.

HIV transcriptase inhibitor

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, deravirdine, deravirdine mesylate, doravirine, efavirenz, azovirine, lentinan, vitamin Lapin, Lipivirin, AIC-292, KM-023 and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include antifovir, antifovir disoproxil, emtricitabine, tenofovir, tenofovir alafenamide, rich Tenofovir alafenamide maleate, tenofovir alafenamide hemi-fumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir hemi-fumarate nofovir disoproxil, VIDEX ^® and VIDEX EC ^® (Didaroxin, ddl), abacavir, abacavir sulfate, alorofudine, alitabine, censavudine, Didanoxin , efcitabine, fintenavir, fosaferdine, fosaferdine, lamevudine, phosphine azide, stafodine, dideoxycytidine, chiffudine and KP-1461 .

HIV integrase inhibitor

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, cichoric acid, derivatives of cichoric acid, 3,5-dicaffeoic acid, 3,5-dicaffinchinal Acid derivatives, rose red tricarboxylic acid, rose red tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tivostin, tivostin derivatives, quercetin Quercetin, derivatives of quercetin, raltegravir, dotegravir, JTK-351 and cabotegravir.

Examples of HIV non-catalytic (or ectopic) integrase inhibitors (NCINI) include CX-05045, CX-05168, T-169 and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include sanivirol, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aviroc, viveroc, maveroc, sanivirol, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include albovirtide, envoviride, and sylvoviride.

Examples of CD4 attachment inhibitors include ibaloma.

Examples of gp120 inhibitors include Radha-108 (receptol) and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor and vMIP (Haimipu).

HIV maturation inhibitor

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

latent reverse agent

Examples of latent reversers include histone deacetylase (HDAC) inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BET-bromodomain 4 (BRD4) Inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, dishulan, amphotericin B and GSK- 343.

Examples of HDAC inhibitors include midesin, vorinostat, and panobinostat.

Examples of PKC activators include lactamide, plastron, ingenol B, and DAG-lactone.

capsid inhibitor

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid interfering compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azo[di]formamide and HIV p24 capsid protein inhibitors.

Immunotherapy

Examples of immunotherapy include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 , Pd-1) modulator; Programmed death-ligand 1 (programmed death-ligand 1, Pd-L1) modulator; IL-15 antagonist; DermaVir; Interleukin-7; Chloroquinine (hydroxychloroquine); Prukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil Ester (MPA) and its ester-derived mycophenolate mofetil (MMF); ribavirin; polyethyleneimine (PEI); 1; MOR-22; GS-9620; BMS-936559; and IR-103.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include ederalisib, alpelisib, buparis, CAI orotate, copalis, duveris, gedatolisib, neratinib, panulisib, peliversib, picris, pilaris Silk, Praquintinib mesylate, Rigosert, Rigosert sodium, Sonorizib, Tasilix, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457 , CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV -1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS- 5584, XL-765 and ZSTK-474.

HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

Examples of HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins include DARTs®, ^DUOBODIES® , ^BITES® , ^XmAbs® , ^TandAbs® , Fab derivatives, BMS- ⁹³⁶⁵⁵⁹ , TMB-360 and antibodies against HIV gp120 or gp41 thing.

Examples of those directed against HIV gp120 or gp41 include bavitosimab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (implimumab ), VRC01, A32, 7B2, 10E8, VRC-07-523, MGD-014 and VRC07.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

other therapeutic agents

Examples of other therapeutic agents include those disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences) ; WO 2013/091096 (Boehringer Ingelheim); and U.S. Compounds of 20100143301 (Gilead Sciences).

HIV vaccine

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4 derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120 ) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Ramine, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multilayer DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN , NAcGM3/VSSP ISA-51, multi-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV(FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT -20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX -B21, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX -101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and viroid vaccines are like viroid vaccines.

HIV combination therapy

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with ^ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ^® (EVIPLERA ^® ; lipivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD ^® (elvitegravir, cobicita, tenofovir disoproxil fumarate pyrifurate and emtricitabine); TRUVADA ^® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); antifovir; antifovir disoproxil; test Viceta; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir hemifumarate fovir alafenamide; TRIUMEQ ^® (dotegravir, abacavir, and lamevudine); dotegravir, abacavir sulfate, and lamevudine; raltegravir; raltegravir and lamevudine; maveroc; envoviride; ALUVIA ^® (KALETRA ^® ; lopinavir and ritonavir); COMBIVIR ^® (chivudine and lamevudine; AZT+3TC); EPZICOM ^® ( LIVEXA ^® ; abacavir sulfate and lamevudine; ABC+3TC); TRIZIVIR ^® (abacavir sulfate, chivudine and lamevudine; ABC+AZT+3TC); Ling hydrochloride; Antanavir sulfate and Cobicita; Antanavir and Cobicita; Darunavir and Cobicita; Antanavir; Antanavir sulfate; Doteg Vitriol; elvitegravir; ritonavir; antanavir sulfate and ritonavir; darunavir; lamevudine; plastine; Viren; Iszovirin; Fenavir; Fenavir mesylate; Interferon; Didanoxin; Stafferdin; Indinavir; Vudine; Chivudine; Virapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Dideoxycytidine; Tipnavir; Amperavir; Delavidine; Delavidin Vitinol mesylate; Radha-108 (receptol); Hlviral; Lamevudine and Tenofovir disoproxil fumarate; Efavirenz, Lamevudine and Tenofovir disoproxil fumarate Ester; phosphine azide; lamevudine, verapine, and chivudine; abacavir; and one, two, three, four or more other therapeutic agent combinations of abacavir sulfate.

In particular embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are conjugated to HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are conjugated to HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In additional embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetics Enhancer binding. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor, integrase inhibitor, and pharmacokinetic enhancer of reverse transcriptase. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is conjugated to two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir fumarate Disoproxil, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate were combined.

In particular embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil Nofovir alafenamide or tenofovir alafenamide hemi-fumarate conjugate.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a compound selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenol fumarate The first other therapeutic agent of the group consisting of fovir dipivoxil, tenofovir alafenamide and tenofovir alafenamide hemifumarate and selected from the group consisting of emtricitabine and lamevudine The second other therapeutic agent of the group is combined.

In particular embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a compound selected from the group consisting of tenofovir, tenofovir disoproxil, and tenofovir disoproxil fumarate The combination of the first other therapeutic agent and the second other therapeutic agent of the group consisting of tenofovir alafenamide and tenofovir alafenamide hemifumarate, wherein the second other therapeutic agent is emtricitabine .

A compound disclosed herein (eg, any compound of formula (I)) can be combined with one or more other therapeutic agents at any dose of a compound of formula (I) (eg, 50 mg to 1000 mg of a compound).

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate amine or tenofovir alafenamide, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30 Or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or Tenofovir alafenamide, combined with 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or Tenofovir alafenamide, combined with 200 mg of emtricitabine. A compound disclosed herein (eg, a compound of formula (I)) can be combined with an agent disclosed herein in any dose of the compound (eg, 50 mg to 500 mg of a compound), such as listing each dose combination specifically and individually.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 to 400 mg of tenofovir disoproxil fumarate, tenofovir hemifumarate Disoproxil or tenofovir disoproxil, and 200 mg of emtricitabine were combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; Or 250 to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine combined. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or Tenofovir disoproxil, combined with 200 mg of emtricitabine. A compound disclosed herein (eg, a compound of formula (I)) can be combined with an agent disclosed herein in any dose of the compound (eg, 50 mg to 500 mg of a compound), such as listing each dose combination specifically and individually.

In a certain embodiment, provided is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (eg, one, two, three, one or two, or one to three) other treatments set of medicines.

Manufacture of kits and objects

The present disclosure relates to a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, eg, for inhibiting HIV reverse transcriptase, such as for the treatment of HIV infection or AIDS or as a research tool. Instructions for use are ordinary written instructions, but electronic storage media (such as magnetic disks or CD-ROMs) containing instructions are also acceptable.

The present disclosure pertains to pharmaceutical kits comprising one or more containers comprising any compound of formula (I), or a pharmaceutically acceptable salt thereof. This container may be associated in any combination with a notice form prescribed by a governmental agency regulating the manufacture, use, or sale of the drug, which notice indicates approval for human consumption by the agency of manufacture, use, or sale. The ingredients (if more than one ingredient) may be contained in separate containers or together when cross-reactivity and shelf-life permit. These ingredients can be combined in one container. Kits can be in unit dosage form, in bulk (eg, multi-dose packs), or sub-unit doses. A kit may also contain multiple unit doses of the compound and instructions for use and packaged in quantities sufficient for storage and use in pharmacies (eg, hospital pharmacies and compounding pharmacies).

Also disclosed are articles of manufacture comprising any compound of formula (I), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the relevant art, eg, vials, jars, ampoules, bottles, jars, flexible packaging, and the like. The article of manufacture can be further sterilized and/or sealed.

The present disclosure is also directed to processes and intermediates that facilitate the preparation of a target compound or a pharmaceutically acceptable salt thereof.

A number of general references are available that provide commonly known chemical synthesis schemes and conditions that facilitate the synthesis of disclosed compounds (see Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, Wiley-Interscience, 2013).

The compounds described herein can be purified by any means known in the relevant art, including chromatography, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography Chromatography (flash column chromatography) and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases and ionic resins. Most of the disclosed compounds are typically purified by silica gel and/or alumina chromatography. See Introduction to Modern Liquid Chromatography, 2nd ed., ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

In any process for preparing a target compound, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by means of common protecting groups as described in standard practice (such as TWGreene and ^PGMWuts , "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006). Protecting groups can be removed at a convenient subsequent stage using methods known in the relevant art.

Exemplary chemical entities useful in the methods of the Examples will now be described by reference to the schematic synthetic schemes for their general preparations herein and subsequent specific examples. The skilled artisan will recognize that in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the ultimate desired substituent is carried through the reaction scheme, with or without protection, to appropriately produce the desired product. Alternatively, where a substituent is ultimately desired, a suitable group that can be carried through the reaction scheme may be required and/or intended and substituted appropriately with the desired substituent. Further, those of ordinary skill in the relevant art will recognize that the transformations shown in the following figures can be performed in any order that is compatible with the functionality of the particular pendant group. Each of the reactions depicted in the general scheme works best from about 0°C to the reflux temperature of the organic solvent used. Unless otherwise specified, the variables are as defined with reference to formula (I) above.

Representative syntheses for compounds of the present disclosure are described in the following schemes, with detailed examples.

Embodiments are also directed to processes and intermediates that facilitate the preparation of the target compounds or pharmaceutically acceptable salts thereof.

A number of general references are available that provide commonly known chemical synthesis schemes and conditions that facilitate the synthesis of disclosed compounds (see Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, Wiley-Interscience, 2013.). Angew. Chem. Int. Ed. 2014, 53, 2-21, the disclosure of which is hereby incorporated by reference in its entirety, provides a review of sulfur (VI) fluoride exchange, which may also be useful in synthetic schemes .

The compounds described herein can be purified by any means known in the relevant art, including chromatography, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange Chromatography. Any suitable stationary phase can be used, including normal and reversed phases and ionic resins. Most of the disclosed compounds are typically purified by silica gel and/or alumina chromatography. See Introduction to Modern Liquid Chromatography, 2nd ed., ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

In any process for preparing a target compound, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by means of common protecting groups as described in standard practice (such as TWGreene and ^PGMWuts , "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006). Protecting groups can be removed at a convenient subsequent stage using methods known in the relevant art.

Exemplary chemical entities useful in the methods of the Examples will now be described by reference to the schematic synthetic schemes for their general preparations herein and subsequent specific examples. The skilled artisan will recognize that in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the ultimate desired substituent is carried through the reaction scheme, with or without protection, to appropriately produce the desired product. Alternatively, where a substituent is ultimately desired, a suitable group that can be carried through the reaction scheme may be required and/or intended and substituted appropriately with the desired substituent. Further, those of ordinary skill in the relevant art will recognize that the transformations shown in the following figures can be performed in any order that is compatible with the functionality of the particular pendant group. Each of the reactions depicted in the general scheme can be run from about 0°C to the reflux temperature of the organic solvent used. unless specifically stated Otherwise, the variables refer to the definitions of formula (I) above.

Representative syntheses for compounds of the present disclosure are described in the following schemes, with detailed examples.

Scheme 1 shows a representative synthesis of the example compounds. This methodology is compatible with a wide variety of functionalities.

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ and Q are as defined herein. Also in Scheme 1, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor molecular groups that form appropriate linkages and molecular groups in formula (I). Starting materials can be obtained from commercial sources or via well-established synthetic procedures. Chemical formulas 1-D are discussed in Schemes 4 and 5 below.

In Scheme 1, a nucleophilic substitution reaction occurs between Formulas 1-A and 1-B to produce compounds of Formula 1-C. The amine group of formula 1-B reacts with formula 1-A to replace Y ^1a , where Y ^1a is a leaving group, such as halogen, triflate, mesylate and toluenesulfonic acid Salt (tosylate). In certain instances, Y ^1a is halogen, such as iodo, bromo or chloro.

。在某些例子中，耦合步驟包含鈀催化劑，像是1,1'-雙(二第三丁基膦基)二茂鐵二氯化鈀(1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride)或1,1'-雙(二苯基膦基)二茂鐵二氯化鈀(1,1'-bis(diphenylphosphino)ferrocene palladium dichloride)。 With continued reference to Scheme 1, a coupling reaction occurs between Formulas 1-C and 1-D to produce compounds of Formula (I). In certain instances, a palladium-catalyzed reaction between an aryl halide and an organoboron compound (eg, a Suzuki coupling reaction) can be used. Using the Suzuki coupling reaction, Z ^1a in Formula 1-C may be a halide, such as iodo or bromine, and Z ^2a in Formula 1-D may be boronic acid or boronate. In some cases, Z ^2a is

. In some instances, the coupling step includes a palladium catalyst such as 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1,1'-bis(di- tert -butylphosphino) ferrocene palladium dichloride) or 1,1' - bis(diphenylphosphino)ferrocene palladium dichloride.

Continuing with reference to Scheme 1, as an alternative coupling reaction between formulas 1-C and 1-D, a palladium-catalyzed reaction (eg, Stille coupling reaction) between organoboron compounds and aryl halides can be used for A compound of formula (I) is produced. Using Stiller coupling reaction, Z ^1a in formula 1-C can be an organotin molecular group (-SnR ₄ , where R is an alkyl group) and Z ^2a in formula 1-D can be a halide such as iodo or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0) (bis(tri- tert -butylphosphine)palladium(0)).

Scheme 2 is another synthetic method representative of the example compounds. This methodology is compatible with a wide variety of functionalities.

Scenario 2

In Scheme 2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X ¹ , X ² , X ³ and Q are as defined herein . Also in Scheme 2, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor molecular groups for forming appropriate bonds and molecular groups in formula (I). Starting materials can be obtained from commercial sources or via well-established synthetic procedures.

In Scheme 2, a nucleophilic substitution reaction between Formula 2-A and 2-B occurs to produce a compound of Formula 2-C. The amine group of formula 2-B reacts with formula 2-A to replace Y ^1a , which is a leaving group such as halogen, triflate, mesylate, and tosylate. In certain instances, Y ^1a is halogen, such as iodo, bromo or chloro.

。在某些例子中，耦合步 驟包含鈀催化劑，像是1,1'-雙(二第三丁基膦基)二茂鐵二氯化鈀或1,1'-雙(二苯基膦基)二茂鐵二氯化鈀。 Continuing with reference to Scheme 2, a coupling reaction between Formulas 2-C and 2-D occurs to produce compounds of Formula 2-E. In certain instances, palladium-catalyzed reactions between aryl halides and organoboron compounds (eg, Suzuki coupling reactions) can be used. Using the Suzuki coupling reaction, Z ^1a in Chemical Formula 2-C may be a halide, such as iodo or bromine, and Z ^2a in Chemical Formula 2-D may be boronic acid or boronate. In some cases, Z ^2a is

. In certain instances, the coupling step comprises a palladium catalyst, such as 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride or 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride.

Continuing with reference to Scheme 2, as an alternative coupling reaction between formulas 2-C and 2-D, a palladium-catalyzed reaction (eg, Stiller coupling reaction) between an organoboron compound and an aryl halide can be used to generate formula ( Compounds of I). Using Stiller coupling reaction, Z ^1a in formula 2-C can be an organotin molecular group (-SnR ₄ , where R is an alkyl group) and Z ^2a in formula 2-D can be a halide such as iodo or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0) (bis(tri- tert -butylphosphine)palladium(0)).

Continuing with reference to Scheme 2, a coupling reaction between formula 2-D and 2-E occurs to yield compounds of formula (I). In certain instances, coupling reactions between stabilized phosphonate carbanions and aldehydes (eg, Horner-Wadsworth-Emmons reactions) can be used.

Scheme 3 is another synthetic method representative of the example compounds. This methodology is compatible with a wide variety of functionalities.

Scenario 3

In Scheme 3, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ and Q are as defined herein. Also in Scheme 3, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor molecular groups for forming appropriate bonds and molecular groups in formula (I). Starting materials can be obtained from commercial sources or via well-established synthetic procedures. The synthesis of Formula 1-D will be discussed in Schemes 4 and 5.

。在某些例子中，耦合步驟包含鈀催化劑，像是1,1'-雙(二第三丁基膦基)二茂鐵二氯化鈀或1,1'-雙(二苯基膦基)二茂鐵二氯化鈀。 Referring to Scheme 3, a coupling reaction between Formula 3-A and 1-D occurs to produce Formula 3-B. In certain instances, palladium-catalyzed reactions between aryl halides and organoboron compounds (eg, Suzuki coupling reactions) can be used. Using the Suzuki coupling reaction, Z ^1a in Chemical Formula 3-A may be a halide, such as iodo or bromine, and Z ^2a in Chemical Formula 1-D may be boronic acid or boronic acid ester. In some cases, Z ^2a is

. In certain instances, the coupling step comprises a palladium catalyst, such as 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride or 1,1'-bis(diphenylphosphino) Ferrocene palladium dichloride.

Continuing with reference to Scheme 3, as an alternative coupling reaction between formulas 3-A and 1-D, a palladium-catalyzed reaction (eg, Stiller coupling reaction) between an organoboron compound and an aryl halide can be used to generate formula ( Compounds of I). Using Stiller coupling reaction, Z ^1a in formula 1-C can be an organotin molecular group (-SnR ₄ , where R is an alkyl group) and Z ^2a in formula 1-D can be a halide such as iodo or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphino)palladium(0).

With continued reference to Scheme 3, a nucleophilic substitution reaction between Formulas 3-B and 3-C occurs to produce compounds of Formula (I). The amine group of formula 3-C reacts with formula 3-B to replace Y ^1a , which is a leaving group such as halogen, triflate, mesylate, and tosylate. In certain instances, Y ^1a is halogen, such as iodo, bromo or chloro.

Scheme 4 shows a representative synthesis of Formula 1-D. This methodology is compatible with a wide variety of functionalities.

In Scheme ⁴ , ^R7 , ^R8 , ^R9 , R10 and Q are as defined herein. Also in Scheme 4, as discussed below, Q ^1a , X ^1a , and X ^2a are precursor molecular groups for forming appropriate bonds and molecular groups in Formula 1-D. Starting materials can be obtained from commercial sources or via well-established synthetic procedures.

In Scheme 4, a coupling reaction between Formula 4-A and 4-B occurs to produce Formula 4-C. In certain instances, palladium-catalyzed reactions between aryl halides and olefinic compounds (eg, Heck coupling reactions) can be used. Using the Heck coupling reaction, X ^1a in Chemical Formula 4-A may be a halide, such as iodo or bromo, and X ^2a in Chemical Formula 4-B may be hydrogen. The Heck coupling reaction can be carried out in the presence of a palladium catalyst, such as palladium(II) acetate with tri( o -tolyl)phosphine.

。在某些例子中，硼基化步驟包含鈀催化劑，像是伴隨二環己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦(dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine)的醋酸鈀(II)。可使用其他的硼基化反應。 Continuing to refer to Scheme 4, Q ^1a in Chemical Formulas 4-A and 4-C is a precursor molecular group of boronic acid or boronic ester in Chemical Formula 1-D, wherein Z ^2a is boronic acid or boronic ester. A borylation reaction of Formula 4-C occurs to yield compounds of Formula 1-D. In some instances, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane)( Cross-coupling reaction of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)) with aryl halides (e.g. Miyaura (Miyaura) boronylation reaction). Using the Miyaura boronylation reaction, Q ^1a in Formula 4-C can be a halide, such as iodo or bromo. In certain instances, Formula 4-C can be combined with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-di(1,3,2-di) borane) to provide Formula 1-D, where Z ^2a is

. In some instances, the boronylation step involves a palladium catalyst such as dicyclohexyl (2',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine) of palladium(II) acetate. Other boronylation reactions can be used.

Scheme 5 shows a representative synthesis of Formula 1-D. This methodology is compatible with a wide variety of functionalities.

In Scheme ⁵ , ^R7 , ^R8 , ^R9 , R10 and Q are as defined herein. Also in Scheme 5, as discussed below, Q ^1a and X ^1a are precursor molecular groups to form appropriate bonds and molecular groups in Formula 1-D. Starting materials can be obtained from commercial sources or via well-established synthetic procedures.

In Scheme 5, a coupling reaction between Formulae 5-A and 5-B occurs to produce Formula 5-C. In certain instances, coupling reactions between stable phosphonate carbanions and aldehydes (eg, the Horner-Wadsworth-Emmons reaction) can be used. Using the Horner-Wadsworth-Emmons reaction, X ^1a in Formula 4-A can be an aldehyde or a ketone (eg, X ^1a is -CHO or -C(O)R ⁹ ).

。在某些例子中，硼基化步驟包含鈀催化劑，像是伴隨二環己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦(dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine)的醋酸鈀(II)。可使用其他的硼基化反應。 Continuing to refer to Scheme 5, Q ^1a in chemical formula 5-A and 5-C is a precursor molecular group of boronic acid in chemical formula 1-D, wherein Z ^2a is boronic acid. The boronylation reaction of Formula 5-C occurs to produce compounds of Formula 1-D. In certain instances, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane) can be used with Cross-coupling reactions of aryl halides (eg Miyaura boronylation). Using the Miyaura boronylation reaction, Q ^1a in Formula 5-C can be a halide such as iodo or bromo. In certain instances, Formula 5-C can be combined with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-di(1,3,2-di) borane) to provide Formula 1-D, where Z ^2a is

. In some instances, the boronylation step involves a palladium catalyst such as dicyclohexyl (2',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine) of palladium(II) acetate. Other boronylation reactions can be used.

之化合物與化學式：

之化合物反應；從而產生化學式

之化合物，其中R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、X¹、X²、X³、Z^1a、Z^2a及Q為如本文定義的。 Accordingly, as also described in greater detail herein, the present disclosure pertains to processes for preparing the compounds of the present disclosure, which process involve converting the chemical formula:

The compound and chemical formula:

the compounds react; resulting in the chemical formula

^{The compound} wherein ^R1 , R2, ^R3 , R4, ^R5 , ^R6 , ^R7 , ^R8 , ^X1 , ^X2 , ^X3 , ^Z1a , ^Z2a and Q are as defined herein.

之化合物與化學式：

之化合物反應；從而產生化學式

之化合物，其中R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、X¹、X²、X³、Y^1a及Q為如本文定義的。 Accordingly, as also described in greater detail herein, the present disclosure pertains to processes for preparing the compounds of the present disclosure, which process involve converting the chemical formula:

The compound and chemical formula:

the compounds react; resulting in the chemical formula

^{The compound} wherein ^R1 , R2, ^R3 , R4, ^R5 , ^R6 , ^R7 , ^R8 , ^X1 , ^X2 , ^X3 , ^Y1a and Q are as defined herein.

In certain instances, the above-described processes further involve the step of forming salts of the compounds of the present disclosure. Examples are directed to other processes described herein; and to products made by any of the processes described herein.

Unless otherwise indicated, the methods and techniques of the present embodiments are generally practiced according to conventional methods known in the relevant art and are described in various general and more specific references that are cited and discussed throughout this specification. See Loudon, Organic Chemistry, ^5th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, Wiley-Interscience, 2013.

List of Abbreviations and Acronyms

Abbreviation - Meaning

Ac-Acetyl

B ₂ pin ₂ -4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane)

bs-Broad singlet

°C-Celsius

d-doublet (Doublet)

DCM-dichloromethane (Dichloromethane)

dd- Doublet of doublet

DIPEA-N,N-Diisopropylethylamine (N,N-Diisopropylethylamine)

DMF-N,N-Dimethylformamide (N,N-Dimethylformamide)

DMSO-Dimethylsulfoxide (Dimethylsulfoxide)

dppf-1,1'-bis(diphenylphosphino)ferrocene

dtbpf-1,1'-bis(di-tert-butylphosphino)ferrocene

EC ₅₀ - Half Maximum Effect Concentration

Equiv/eq-equivalent

Et-ethyl

EtOH-ethanol

g-gram

HPLC-High Performance Liquid Chromatography

hrs/h-hour

Hz-Hertz

J-coupling constant

LCMS-liquid chromatography-mass spectrometry

M-Molar concentration (Molar)

m-Multiplet

m/z - mass-to-charge ratio

M+-mass peak

Me-methyl

mg-mg

MHz - Megahertz

min-minute

mL - milliliter

mM - Millimolar concentration (Milimolar)

mm-mm

mmol - millimoles

mol-mol

MS-Mass Spectrometry

MW-Microwave

nM - Nanomolar

NMP-N-Methyl-2-pyrrolidone (N-Methyl-2-pyrrolidone)

NMR - nuclear magnetic resonance

P(oTol) ₃ -tris(o-toluene)phosphine

P(t-Bu) ₃ -tri-tert-butylphosphine

Pd ₂ (dba) ₃ - gins(dibenzylideneacetone)palladium(0)(tris(dibenzylideneacetone)palladium(0))

q-Quartet

quant - quantitative

Rf - Retention Factor

RT/rt/r.t.-room temperature

s-Singlet

sat.-saturated

SPhos-Dicyclohexyl(2',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine

t-triplet (Triplet)

TFA-Trifluoroacetic acid

TMS-Trimethylsilyl

Tr/tr - residence time

UV-ultraviolet

wt.-weight

-4,5-二基)雙(二苯基膦)((9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)) Xantphos-(9,9-Dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine)((9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine))

δ-chemical shift

μL-microliter

μM-Micromolar

μmol-micromolar

The following examples are illustrative only and do not limit the disclosure in any way. Unless otherwise stated, preparative HPLC was performed on a Gilson HPLC system using a 21.2 x 250 mm 10 micron C18 Phenomenex Gemini semi-preparative column with 0.1% trifluoroacetic acid at a flow rate of 20 mL/min. Gradient 0 to 100% acetonitrile mobile phase in water.

The chemical names of all prepared compounds were generated using ChemBioDraw 12.0 software.

When the structures in the following examples are drawn as certain geometric isomers, certain geometric isomers (eg, E or Z isomers) or ratios of E and Z isomers may be described in the title and/or description of the examples Indicated to represent the results of the example.

The following methods described in the examples below were used to purify and characterize certain compounds.

LCMS method 1-Phenomenex Gemini-NX 3u C18 110Å, 100 x 2 mm 3 micron column, acetonitrile with 0.1% formic acid, water with 0.1% formic acid; 0 min-7.0 min 0-100% ACN, flow rate 0.5 mL/min.

LCMS method 2 - Gemini 5u C18 110Å, 50 x 4.60mm 5 micron column, acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; gradient: 0min-3.5min 5-100% ACN; flow rate 2mL/min .

LCMS method 3 - Kinetex 2.6μ C18 100A, 50 x 3.00mm column, acetonitrile with 0.1% formic acid, water with 0.1% formic acid; gradient: 0min-1.4min 2-100% CAN, 1.4min-1.8min 100% ACN, 1.8min-1.85min 100%-2% ACN, 1.85min-2min 2% ACN, flow rate 1.8mL/min.

Example 1

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)benzonitrile (( E )-4 -((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 1

Step 1: Synthesis of 4-((8-bromoquinazolin-2-yl)amine)benzonitrile (4-((8-bromoquinazolin-2-yl)amino)benzonitrile) (Compound 1a)

8-bromo-2-chloroquinazoline (1.0 g, 4.10 mmol, Ark Pharm Inc, AK-27609) in isopropanol (15 mL) was combined with 4-cyanoaniline (4 -cyanoaniline) was heated at reflux for 15 hours. The solid product was filtered off and washed twice with cold isopropanol (2 x 10 mL). The product was dried in air to provide the title compound 1a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.76(s,1H), 9.47(s,1H), 8.41(d, J =8.8Hz,2H), 8.28(dd, J =7.8,1.2Hz,1H ), 8.06(dd, J =7.8, 1.2Hz, 1H), 7.85(d, J =8.8Hz, 2H), 7.44(t, J =7.8Hz, 1H). HRMS: Calculated (ESI+) for _C15H10N4Br [M ₊ H] _325.00834 , found 325.00821. LCMS (m/z) 325.0 [M+H], Tr=4.69 min (LCMS method 1).

Step 2: Synthesis of ( E )-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (( E )-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile) (Compound 1b )

Palladium(II) acetate (112mg, 0.5mmol), acrylonitrile (531mg, 10mmol), tris(o-toluene)phosphine (131mg, 0.5mmol) and triethylamine (4mL, 30mmol) were added to anhydrous acetonitrile (25mL) ) in 2,5-dibromo-1,3-dimethylbenzene (2,5-dibromo-1,3-dimethylbenzene) (2640 mg, 10 mmol, Oakwood Products, Inc.-018507), then the mixture was heated with argon Air flushed and heated at 110°C for 2 hours. The reaction mixture was filtered through Celite and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and then redissolved in ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was extracted again with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. This was chromatographed on silica gel (gradient from 0 to 20% ethyl acetate in isohexane) to provide the crude product, which was treated with hexanes (10 mL) in a sonic bath for 10 minutes. The product precipitated out of solution and was collected by filtration. The solid was washed with cold hexane to provide compound lb. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25 (d, J = 16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J = 16.6 Hz, 1 H), 2.42 (s, 6H). No MS signal by LCMS (m/z), Tr=2.78min (LCMS method 2).

Step 3: Synthesis of ( E )-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-oxoboron-2-yl)phenyl) Acrylonitrile (( E )-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile) (Compound 1c)

Compound 1b (391 mg, 1.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane ) (630 mg, 2.48 mmol), potassium carbonate (687 mg, 5 mmol), palladium (II) acetate (19 mg, 0.08 mmol) and dicyclohexyl (2 in dry N,N-dimethylformamide (20 mL) A mixture of ',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine (SPhos, 85 mg, 0.21 mmol) was flushed with argon and heated at 100 °C for 1 hour. The reaction mixture was filtered through Celite and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and then redissolved in ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was extracted again with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered under reduced pressure and concentrated to give a crude residue. It was purified by silica gel chromatography (gradient from 0 to 20% ethyl acetate in isohexane) to provide compound 1c . ¹ H NMR (400MHz, CDCl ₃ )δ 7.28(d, J =16.6Hz, 1H), 7.00(s, 2H), 5.84(d, J =16.6Hz, 1H), 2.39(s, 6H), 1.37( s,12H).LCMS(m/z)284.3[M+H],Tr=2.85min(LCMS method 2)

Step 3: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)benzonitrile (compound 1)

Compound 1a (50 mg, 0.15 mmol), compound 1c (129 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complexed with dichloromethane ) (100 mg, 0.12 mmol), potassium carbonate (64 mg, 0.45 mmol) and copper(I) acetate (19 mg, 0.15 mmol) in dry N,N-dimethylformamide (5 mL) under argon Rinse and heat at 100°C for 15 hours. The solvent was removed under reduced pressure and the crude mixture was chromatographed on silica gel (gradient from 0 to 30% ethyl acetate in isohexane). The crude product was then repurified using HPLC (preparative grade column Phenomenex Gemini 10 micron C18, 250 x 21.2 mm, 10 mL/min, gradient 10 to 100% acetonitrile in water) to provide the title compound 1 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.48(s, 1H), 9.50(s, 1H), 8.09(d, J =7.8Hz, 1H), 7.70-7.87(m, 4H), 7.63(t , J =7.8Hz,1H),7.61(s,2H),7.40(d, J =8.8Hz,2H),6.62(d, J =16.7Hz,1H),1.94(s,6H).HRMS: Calculate (ESI+) for _C26H20N5 [ _M +H] was _402.17132 , found 402.17126. LCMS (m/z) 402.2 [M+H], Tr=4.91 min (LCMS method 1).

Example 2

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)benzonitrile ((( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-compound 2

Step 1: Synthesis of ( E )-3-(4-(4-amine-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )-3-(4 -(4-amino-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 2a)

8-bromo-2-chloroquinazolin-4-amine (8-bromo-2-chloroquinazolin-4-amine) (129mg, 0.5mmol, Ark Pharm Inc, AK-28702), compound 1c (184mg, 0.65mmol) , a mixture of potassium phosphate (potassium phosphate tribasic) (159 mg, 0.75 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (65 mg, 0.10 mmol) under argon Dissolved in a mixture of N,N-dimethylformamide:water (85:15, 40 mL). The reaction was heated to 80°C for 30 minutes. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalents of hexane was added and the mixture was filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the residue was treated with ether in a sonic bath. The solid product was filtered off and washed twice with ether and once with hexane to provide the title compound 2a . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (bs, 2H), 8.28 (dd, J =8.1, 1.6 Hz, 1H), 7.66-7.52 (m, 3H), 7.43 (s, 2H), 6.46 (d, J = 16.7 Hz, 1H), 1.86 (s, 6H). LCMS (m/z) 335.2 [M+H], Tr = 2.48 min (LCMS method 2).

Step 2: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) Benzonitrile (Compound 2)

Compound 2a (100 mg, 0.30 mmol), 4-cyanoaniline (46 mg, 0.388 mmol, Sigma-Aldrich) and N -methyl-2-pyrrolidinone (2 mL) on dry in 1,4-dioxane ( A mixture of hydrogen chloride solution in dioxane) (4M, 7 μL, 0.03 mmol) was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and triethylamine (0.1 mL, 0.72 mmol) was added. After 15 minutes, water (5 mL) was added and the solid product was filtered off and rinsed with water. The crude residue was taken up in a mixture of dichloromethane and diethyl ether (1:1, 5 mL) and then treated in a sonic bath for 3 minutes. The solid compound was filtered off and washed with diethyl ether (5 mL) to provide the title compound 2 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.44(s, 1H), 8.18(dd, J =8.2, 1.5Hz, 1H), 7.74(d, J =16.7Hz, 1H), 7.70(d, J =8.9Hz,2H),7.51(s,2H),7.48(dd, J =7.1,1.3Hz,1H),7.34(dd, J =8.2,7.1Hz,1H),7.26(d, J =8.9Hz , 2H), 6.54(d, J =16.7Hz, 1H), 1.91(s, 6H).HRMS: Calculated (ESI+) of C ₂₆ H ₂₁ N ₆ [M+H] is 417.1822, found 417.1820. LCMS (m/z) 417.2 [M+H], Tr=4.68 min (LCMS method 1).

Example 3

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-2-methyl Oxybenzonitrile (( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methoxybenzonitrile)-compound Object 3

Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amine)-2-methoxybenzonitrile hydrochloride (4-((4-amino-8-bromoquinazolin-2 -yl)amino)-2-methoxybenzonitrile hydrochloride) (compound 3a)

8-Bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, Ark Pharm Inc, AK-28702) and 4-amine-2-methoxybenzonitrile (4-amine-2-methoxybenzonitrile (4) in isopropanol (7 mL) -amino-2-methoxybenzonitrile) (222 mg, 1.5 mmol, Ark Pharm Inc, AK-77827) was heated in a microwave at 180°C for 8 hours. The reaction mixture was cooled to room temperature and the solid product was filtered off and washed with cold isopropanol followed by diethyl ether and hexane to provide compound 3a as a salt of HCl. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.24(d, J =8.1Hz,1H), 8.07(d, J =7.6Hz,1H), 7.59(d, J =8.5Hz,1H), 7.42( dd, J =8.6,1.9Hz,1H),7.37-7.04(m,5H),3.99(s,3H).LCMS(m/z)370.3[M+H],Tr=2.43min(LCMS method 2) .

Step 2: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) -2-Methoxybenzonitrile (Compound 3)

Compound 3a (50 mg, 0.14 mmol), compound 1c (76 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complexed with dichloromethane ) (33 mg, 0.04 mmol), tripotassium carbonate (86 mg, 0.41 mmol), and copper(I) acetate (2 mg, 0.01 mmol) in dry N,N-dimethylformamide (5 mL) under argon Air flushed and heated at 120°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane was added and the mixture was filtered through a 3 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the crude mixture was subjected to silica gel chromatography (gradient from 5 to 50% ethyl acetate in isohexane). The product was then repurified by reverse phase chromatography (5 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) to provide compound 3 as the TAF salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.25 (bs, 1H), 7.74-7.65 (m, 2H), 7.62-7.42 (m, 5H), 7.30 (d, J =9.0Hz, 2H), 7.26 -6.95(m,1H),6.53(d, J =17.0Hz,1H),3.41(s,3H),1.93(s,6H).LCMS(m/z)447.4[M+H],Tr=2.39 min (LCMS method 2).

Example 4

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine)benzonitrile ((( E )-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile)-compound 4

Step 1: Synthesis of 4-((8-bromo-6-fluoroquinazolin-2-yl)amine)benzonitrile (4-((8-bromo-6-fluoroquinazolin-2-yl)amino)benzonitrile)(compound 4a)

8-bromo-2-chloro-6-fluoroquinazoline (8-bromo-2-chloro-6-fluoroquinazoline) (500mg, 1.91mmol, Ark Pharm Inc, AK-93358) and N-methylpyrrole in dry A mixture of 4-aminobenzonitrile (250 mg, 2.12 mmol, Sigma-Aldrich) in pyridone was heated in a microwave at 200°C for 5 hours. The reaction mixture was cooled to room temperature and treated with silica gel chromatography (gradient from 5 to 50% ethyl acetate in isohexane) to provide the title compound 4a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.69(s, 1H), 9.37(s, 1H), 8.32(d, J =8.7Hz, 2H), 8.26(dd, J =8.5, 2.7Hz, 1H ), 7.86(dd, J =8.5,2.7Hz,1H),7.78(d, J =8.7Hz,2H).LCMS(m/z)343.0[M+H],Tr=4.72min(LCMS method 1) .

Step 2: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine) benzonitrile (compound 4)

Compound 4a (50 mg, 0.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane) ) (40 mg, 0.16 mmol), potassium acetate (60 mg, 0.61 mmol) and [1,1'-bis(diphenylene) complexed with dichloromethane in dry N,N-dimethylformamide (5 mL) A mixture of phosphino)ferrocene]palladium(II) dichloride (50 mg, 0.061 mmol) was flushed with argon and heated at 100 °C for 1 hour. Compound 1b, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (50 mg, 0.061 mmol) and potassium carbonate (90 mg, 0.65 mmol) complexed with dichloromethane ) was added to the reaction mixture. The reaction mixture was heated to 100°C for 5 hours, cooled to room temperature, concentrated under reduced pressure and subjected to silica gel chromatography (gradient from 5 to 50% ethyl acetate in isohexane). The crude product was then repurified using HPLC (preparative grade column Phenomenex Gemini 10 micron C18, 250 x 21.2 mm, 10 mL/min, gradient 10 to 100% acetonitrile in water) to provide title compound 4 . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.45(s, 1H), 7.92-7.86(m, 1H), 7.82-7.76(m, 2H), 7.72(s, 1H), 7.68(d, J = 8.9Hz, 2H), 7.58(s, 2H), 7.36(d, J =8.9Hz, 2H), 6.60(d, J =16.7Hz, 1H), 1.92(s, 6H).LCMS(m/z) 420.1 [M+H], Tr=4.85 min (LCMS method 1).

Example 5

( E )-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amine)benzonitrile (( E )-4- ((8-(4-(2-Cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 5 (mixture E / Z = 4/1)

Step 1: Synthesis of 4-((8-(2,6-difluoro-4-carboxyphenyl)quinazolin-2-yl)amine)benzonitrile (4-((8-(2,6- difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile) (compound 5a)

Compound 1a (40 mg, 0.12 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-diboran-2-yl)benzaldehyde (3 , 5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde) (66 mg, 0.24 mmol, Sigma-Aldrich) and in tetrahydrofuran/water mixture (10 : A mixture of potassium fluoride (24 mg, 0.4 mmol) in 1, 10 mL) was flushed with argon and tri-tert-butyl was added after addition of bis(dibenzylideneacetone)palladium(0) (68 mg, 0.07 mmol). Phosphine (36 μL, 0.14 mmol). The mixture was heated at 80°C for 4 hours. The solvent was removed under reduced pressure and the crude mixture was purified by silica gel chromatography (gradient from 20 to 80% ethyl acetate in isohexane) to provide the title compound 5a. ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.55(s, 1H), 10.15(s, 1H), 9.51(s, 1H), 8.16(d, J =8.0Hz, 1H), 8.03(d, J =7.0Hz,1H),7.90(d, J =6.9Hz,2H),7.83(d, J =8.8Hz,2H),7.67-7.58(m,1H),7.53(d, J =8.8Hz,2H) ).LCMS (m/z) 387.1 [M+H], Tr=4.67 min (LCMS method 1).

Step 2: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amine)benzonitrile (Compound 5 ) (mixture E / Z = 4/1)

Cesium carbonate (1.5 g, 4.6 mmol) was added to compound 5a (70 mg, 0.18 mmol) and diethyl (cyanomethyl) phosphonate in dry dichloromethane (25 mL). cyanomethyl)phosphonate) (32 μL, 0.2 mmol) and the solvent was slowly removed under reduced pressure at 30°C. The resulting reaction mixture was left at room temperature overnight. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (preparative grade column Phenomenex Gemini 10 micron C18, 250 x 21.2 mm, 10 mL/min, gradient 10 to 100% acetonitrile in water) to provide as E / Z isomer The title compound 5 in a 4/1 mixture. ^1H NMR for the E isomer (400MHz, _DMSO - d6 )δ 10.54(s,1H), 9.49(s,1H), 8.16-8.12(m,1H), 8.0(d, J =7.3Hz ,1H),7.87-7.83(m,3H),7.73(d, J =8.0Hz,2H),7.63-7.58(m,1H),7.56-7.52(m,2H),6.81(d, J =16.7 Hz,1H).LCMS(m/z)410.1[M+H],Tr=4.76min (LCMS method 1).

Example 6

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amine)quinazoline-2 -yl)amine)benzonitrile (( E )-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino) benzonitrile) - compound 6

Step 1: Synthesis of 8-bromo-2-chloro- N- (cyclopropylmethyl)quinazolin-4-amine (8-bromo-2-chloro- N- (cyclopropylmethyl)quinazolin-4-amine) (compound 6a)

Cyclopropylmethanamine (95 μL, 1.1 mmol) and N-ethyldiisopropylamine (0.35 mL, 2 mmol) were added to 8-bromo-2 in isopropanol (5 mL). , a solution of 8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol, Ark Pharm Inc., AK-28703). The reaction mixture was stirred at room temperature for 30 minutes. The solid product was filtered off and washed with water (2x5 mL) and pentane (3x5 mL) to provide the title compound 6a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.03 (s, 1H), 8.30 (dd, J =8.3Hz, J =1.3Hz, 1H), 8.12 (dd, J =7.7Hz, J =1.3Hz, 1H), 7.44(t, J =8.0Hz, 1H), 3.41-3.35(m, 2H), 1.23-1.11(m, 1H), 0.52-0.45(m, 2H), 0.34-0.28(m, 2H) .HRMS: Calculated (ESI+) for _C12H12N3BrCl [ _M +H] _311.9898 , found 311.9898. LCMS (m/z) 312.0 [M+H], Tr 4.59 min (LCMS method 1).

Step 2: Synthesis of 4-((8-bromo-4-((cyclopropylmethyl)amine)quinazolin-2-yl)amine)benzonitrile hydrochloride (4-((8-bromo-4- ((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile hydrochloride) (Compound 6b)

A mixture of compound 6a (156 mg, 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180 °C for 2 h. The reaction mixture was cooled to room temperature and the solid product was filtered off and washed twice with cold isopropanol followed by three washes with pentane to provide compound 6b as the HCl salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.39(d, J =7.7Hz, 1H), 8.15-7.99(m, 3H), 7.81(d, J =8.4Hz, 2H), 7.33(t, J =7.9Hz,1H),3.53-3.45(m,2H),1.30-1.17(m,1H),0.54-0.48(m,2H),0.37-0.32(m,2H).HRMS: Calculate C ₁₉ H ₁₇ (ESI+) of _N5Br [M+H] was 394.0662, found 394.0661. LCMS (m/z) 394.0 [M+H], Tr 4.29 min (LCMS method 1).

Step 3: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amine)quinoline oxazolin-2-yl)amine)benzonitrile (compound 6)

Compound 6b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complexed with dichloromethane ) (37 mg, 0.05 mmol) and a mixture of potassium carbonate (104 mg, 0.75 mmol) in a mixture of 1,4-dioxane and water (10:1,5 mL) was flushed with argon and heated at 100 °C 1 hour. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20 to 40% ethyl acetate in isohexane) to provide the title compound 6 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 8.39 (t, J =5.6 Hz, 1H), 8.24-8.13 (m, 2H), 7.74-7.69 (m, 2H), 7.51 (s, 2H), 7.46(dd, J =7.2Hz, J =1.4Hz, 1H), 7.35(t, J =8.2Hz, 1H), 7.26(d, J =8.9Hz, 2H), 6.54(d , J =16.7Hz,1H),3.47-3.43(m,2H),1.90(s,6H),1.30-1.21(m,1H),0.53-0.47(m,2H),0.35-0.30(m,2H) ).HRMS: Calculated (ESI+) for _{C30H27N6 [} M+H] _471.2292 , found 471.2292. LCMS (m/z) 471.2 [M+H], Tr 4.05 min (LCMS method 1).

Example 7

( E )-4-((4-(butylamine)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)benzyl Nitrile (( E )-4-((4-(Butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 7

Step 1: Synthesis of 8-bromo - N -butyl-2-chloroquinazolin-4-amine (compound 7a)

n-Butylamine (109 μL, 1.1 mmol) and N-diisopropylethylamine (0.35 mL, 2 mmol) were added to 8-bromo-2,4-dichloroquinazoline (278 mg) in isopropanol (5 mL). , 1 mmol, Ark Pharm Inc., AK-28703) solution. The reaction mixture was stirred at room temperature for 30 minutes. The solid product was filtered off and washed with water (2x5 mL) and pentane (3x5 mL) to provide the title compound 7a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.87(s, 1H), 8.27(dd, J =8.3Hz, J =1.2Hz, 1H), 8.12(dd, J =7.7Hz, J =1.2Hz, 1H),7.43(t, J =7.9Hz,1H),3.55-3.48(m,2H),1.66-1.57(m,2H),1.41-1.31(m,2H),0.92(t, J =7.3Hz ,3H).HRMS: Calculated (ESI+) for C ₁₂ H ₁₄ N ₃ BrCl[M+H] 314.0054, found 314.0055. LCMS (m/z) 314.0 [M+H], Tr 4.76 min (LCMS method 1).

Step 2: Synthesis of 4-((8-bromo-4-(butylamino)quinazolin-2-yl)amine)benzonitrile hydrochloride (4-((8-bromo-4-(butylamino)quinazolin-2 -yl)amino)benzonitrile hydrochloride) (compound 7b)

A mixture of compound 7a (157 mg, 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180 °C for 2 hours. The reaction mixture was cooled to room temperature and the solid product was filtered off and washed twice with cold isopropanol followed by three times with pentane to provide compound 7b as the HCl salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.32(d, J =7.8Hz, 1H), 8.21-7.79(m, 3H), 7.79(d, J =8.3Hz, 2H), 7.29(t, J =7.8Hz,1H),3.65-3.63(m,2H),1.74-1.59(m,2H),1.43-1.33(m,2H),0.92(t, J =7.4Hz,3H). HRMS: Calculate C (ESI+) for _19H19N5Br [M+H] was _396.0818 , found _396.0816 . LCMS (m/z) 396.1 [M+H], Tr 4.34 min (LCMS method 1)

Step 3: Synthesis of ( E )-4-((4-(butylamine)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl ) amine) benzonitrile (compound 7)

Compound 7b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complexed with dichloromethane ) (37 mg, 0.05 mmol) and a mixture of potassium carbonate (104 mg, 0.75 mmol) in a mixture of 1,4-dioxane and water (10:1,5 mL) was flushed with argon and heated at 100 °C 1 hour. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20 to 40% ethyl acetate in isohexane) to provide the title compound 7 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.45 (s, 1H), 8.25-8.16 (m, 2H), 7.78-7.69 (m, 3H), 7.51 (s, 2H), 7.46 (dd, J = 7.1Hz, J =1.3Hz, 1H), 7.34(t, J =8.2Hz, 1H), 7.27(d, J =8.9Hz, 2H), 6.54(d, J =16.7Hz, 1H), 3.63-3.51 (m,2H),1.90(s,6H),1.72-1.65(m,2H),1.46-1.38(m,2H),0.95(t, J =7.4Hz,3H).MS-ESI ⁺ m/z (%): 473 (100, M+H ⁺ ), 495 (20, M+Na ⁺ ); HRMS: Calculated (ESI+) for C ₃₀ H ₂₉ N ₆ [M+H] 473.2448, found 473.2448. LCMS (m/z) 473.3 [M+H], Tr 4.14 min (LCMS method 1).

Example 8

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amine)benzonitrile (( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile)-compound 8 (mixture E / Z =3/2)

Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amine)benzonitrile (4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile) (compound 8a)

8-Bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, Ark Pharm Inc, AK-28702) and 4-aminobenzonitrile (130 mg, 1.1 mmol, Sigma) in isopropanol (5 mL) -Aldrich) was heated in a microwave at 160°C for 3 hours. The reaction mixture was cooled to room temperature and the solid product was filtered off and washed with cold isopropanol followed by diethyl ether to provide compound 2a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.74(s, 1H), 8.35(d, J =8.8Hz, 2H), 8.16(d, J =8.0Hz, 1H), 8.01(d, J =7.5 Hz, 1H), 7.71(d, J =8.8Hz, 2H), 7.16(t, J =7.8Hz, 1H).HRMS: Calculated (ESI+) for C ₁₅ H ₁₁ N ₅ Br[M+H] is 340.0192 , the measured value is 340.0192. LCMS(m/z)340.0[M+H],Tr=4.06min(LCMS method 1)

Step 2: Synthesis of 4-((4-amino-8-(2,6-difluoro-4-carboxyphenyl)quinazolin-2-yl)amine)benzonitrile (4-((4-amino -8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile) (compound 8b)

Compound 8a (120 mg, 0.36 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-diboran-2-yl)benzaldehyde (285 mg , 1.06 mmol, Sigma-Aldrich) and a mixture of potassium fluoride (102 mg, 1.76 mmol) in a tetrahydrofuran/water mixture (10:1, 30 mL) was flushed with argon and added with bis(dibenzylideneacetone)palladium ( 0) (195 mg, 0.213 mmol) followed by tri-tert-butylphosphine (103 μL, 0.43 mmol). The mixture was heated at 80°C for 4 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20 to 80% ethyl acetate in isohexane) to provide the title compound 8b . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.12(s,1H), 9.56(s,1H), 8.29(dd, J =8.2Hz, J =1.1Hz,2H), 7.87-7.73(m,6H) ), 7.44-7.34 (m, 3H). LCMS (m/z) 401.9 [M+H], Tr=4.28 min (LCMS method 1).

Step 3: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amine)benzyl Nitrile (compound 8) (mixture E / Z = 3/2)

Cesium carbonate (2.5 g, 7.69 mmol) was added to a solution of compound 8b (74 mg, 0.18 mmol) and diethyl(cyanomethyl)phosphonate (30 μL, 0.18 mmol) in dry dichloromethane (25 mL). The solvent was slowly removed from the solution and under reduced pressure at 30°C. The resulting reaction mixture was left at room temperature overnight. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (preparative grade column Phenomenex Gemini 10 micron C18, 250 x 21.2 mm, 10 mL/min, gradient 10 to 100% acetonitrile in water) to provide as E / Z isomer The title compound 8 as a 3/2 mixture. ¹ H NMR for the E isomer (400 MHz, DMSO- d ₆ ) δ 9.54 (s, 1H), 8.29-8.24 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.82-7.78 (m, 2H), 7.72(d, J =7.3, 2H), 7.66(d, J =7.8Hz, 2H), 7.43-7.39(m, 2H), 7.38-7.33(m, 1H), 6.77(d , J =16.7Hz,1H).LCMS(m/z)424.9[M+H],Tr=3.46min (LCMS method 1).

Example 9

( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)cyanopyridine (( E )-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile)-compound 9

Step 1: Synthesis of 5-((4-amino-8-bromoquinazolin-2-yl)amine)2-cyanopyridine (5-((4-amino-8-bromoquinazolin-2-yl)amino)picolinonitrile) (Compound 9a)

8-Bromo-2-chloroquinazolin-4-amine (500 mg, 1.9 mmol, Ark Pharm Inc, AK-28702) and 5-aminopicolinonitrile in isopropanol (10 mL) ) (253 mg, 2.1 mmol, Ark Pharm Inc, AK-26123) was heated in a microwave at 180° C. for 8 hours. The reaction mixture was cooled to room temperature and the solid product was filtered off and washed with cold isopropanol followed by diethyl ether and hexane to provide compound 9a . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.98 (s, 1H), 9.35 (dd, J =2.6, 0.7Hz, 1H), 8.85 (dd, J =8.7, 2.6Hz, 1H), 8.17 (dd , J =8.2,1.3Hz,1H),8.03(dd, J =7.6,1.3Hz,1H),7.95-7.91(m,2H),7.23-7.10(m,2H).LCMS(m/z)343.2 [M+H], Tr=2.31 min (LCMS method 2).

Step 2: Synthesis of ( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) 2-cyanopyridine (compound 9)

Compound 9a (150 mg, 0.44 mmol), compound 1c (498 mg, 1.76 mmol), tripotassium phosphate (560 mg, 2.64 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloride Palladium (57 mg, 0.09 mmol) was dissolved in a mixture of N,N-dimethylformamide:water (85:15, 25 mL) under argon. The reaction was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated. The aqueous layer was washed with additional ethyl acetate. The combined organics were washed twice with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 0 to 40% ethyl acetate and methanol in isohexane (4/1)). The solvent was removed under reduced pressure and the solid residue was treated with a mixture of hexane/diethyl ether (5:1) in a sonic bath for 5 minutes, filtered off and rinsed with hexane to provide the title compound 9 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.70(s, 1H), 8.74(d, J =2.5Hz, 1H), 8.24-8.15(m, 2H), 7.72(d, J =16.7Hz, 1H) ),7.49(d, J =7.6Hz,3H),7.40-7.30(m,2H),6.51(d, J =16.7Hz,1H),1.90(s,6H).LCMS(m/z)418.3[ M+H], Tr=2.47min (LCMS method 2).

Example 10

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)nicotinecarbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl) quinazolin-2-yl)amino)nicotinonitrile)-compound 10

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)nicotine methyl Nitrile (Compound 10)

-4,5-二基)雙(二苯基膦)((9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine))(142mg,0.25mmol)及醋酸鈀(II)(55mg,0.25mmol)在氬氣下於N-甲基-2-吡咯啶酮(40mL)中結合。將反應在120℃下於密封容器中加熱4個小時。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥，加入0.05體積當量的己烷並透過以另外乙酸乙酯清洗的2cm矽膠層過濾此混合物。 減壓濃縮結合的有機物。將粗殘餘物在音波浴中以乙醚/二氯甲烷混合物(1：1)處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物10。¹H NMR(400MHz,DMSO-d ₆)δ 9.58(s,1H),8.57(dd,J=2.4,0.8Hz,1H),8.20(dd,J=8.3,1.4Hz,1H),7.95(dd,J=9.0,0.8Hz,1H),7.73(d,J=16.7Hz,1H),7.55-7.51(m,3H),7.44-7.36(m,2H),6.53(d,J=16.7Hz,1H),1.90(s,6H).LCMS(m/z)418.3[M+H],Tr=1.82min(LCMS方法2)。 Compound 2a (820mg, 2.45mmol), 6-amine nicotine carbonitrile (875mg, 7.35mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (N,N-diisopropylethylamine) (2.53g, 19.6mmol), (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine)((9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine))(142mg, 0.25mmol) and palladium(II) acetate (55 mg, 0.25 mmol) combined in N-methyl-2-pyrrolidone (40 mL) under argon. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.05 volume equivalent of hexane was added and the mixture was filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with a diethyl ether/dichloromethane mixture (1:1) in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 10. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.57 (dd, J =2.4, 0.8Hz, 1H), 8.20 (dd, J =8.3, 1.4Hz, 1H), 7.95 (dd , J =9.0,0.8Hz,1H),7.73(d, J =16.7Hz,1H),7.55-7.51(m,3H),7.44-7.36(m,2H),6.53(d, J =16.7Hz, 1H), 1.90 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr=1.82 min (LCMS method 2).

Example 11

-3-甲腈((E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile)-化合物11 ( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)da

-3-Carbononitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile)- Compound 11

-3-甲腈(化合物11) Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) pyridine

-3-carbonitrile (compound 11)

-3-甲腈(6-aminopyridazine-3-carbonitrile)(22mg,0.18mmol,Matrix Scientific,112287)、N,N-二異丙基乙基胺(62mg,0.47mmol)、(9,9-二甲基-9H-

-4,5-二基)雙(二苯基膦)(3mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(2mL)中結合。將反應在120℃下於密封容器中加熱1個小時。將反應混合物冷卻至室溫並藉由HPLC逆相層析法(帶有0.1%三氟乙酸的0至100%水中乙腈)純化以提供化合物11的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 8.35(bs,1H),8.09(bs,1H),7.78-7.39(m,6H),6.54(d,J=16.7Hz,1H),1.93(s,6H).LCMS(m/z)419.3[M+H],Tr=2.03min(LCMS方法2)。 Compound 2a (20 mg, 0.06 mmol), 6-amine

-3-carbonitrile (6-aminopyridazine-3-carbonitrile) (22mg, 0.18mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine (62mg, 0.47mmol), (9,9-diisopropylethylamine) Methyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (2 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 1 hour. The reaction mixture was cooled to room temperature and purified by HPLC reverse phase chromatography (0 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford compound 11 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.35(bs,1H), 8.09(bs,1H), 7.78-7.39(m,6H), 6.54(d, J =16.7Hz,1H), 1.93(s ,6H).LCMS(m/z)419.3[M+H],Tr=2.03min (LCMS method 2).

Example 12

-2-甲腈((E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile)-化合物12 ( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)pyridine

-2-Carbononitrile (( E )-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile)- Compound 12

-2-甲腈(化合物12) Synthesis of ( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)pyridine

-2-carbonitrile (compound 12)

-2-甲腈(5-aminopyrazine-2-carbonitrile)(22mg,0.18mmol,Ark Pharm Inc,AK-21935)、N,N-二異丙基乙基胺(62mg,0.47mmol)、(9,9-二甲基-9H-

-4,5-二基)雙(二苯基膦)(3mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(1mL)中結合。將反應在120℃下於密封容器中加熱3個小時。將反應混合物冷卻至室溫並藉由逆相層析法(帶有0.1%三氟乙酸的0至100%水中乙腈)純化以提供化合物12的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 8.98(bs,1H),8.36(bs,1H),7.85-7.28(m,6H),6.59(d,J=15.6Hz,1H),1.94(s,6H).LCMS(m/z)419.3[M+H],Tr=1.89min(LCMS方法2)。 Compound 2a (20 mg, 0.06 mmol), 5-aminopyridine

-2-carbonitrile (5-aminopyrazine-2-carbonitrile) (22mg, 0.18mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (62mg, 0.47mmol), (9, 9-Dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (1 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 3 hours. The reaction mixture was cooled to room temperature and purified by reverse phase chromatography (0 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) to provide compound 12 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.98(bs,1H), 8.36(bs,1H), 7.85-7.28(m,6H), 6.59(d, J =15.6Hz,1H), 1.94(s ,6H).LCMS(m/z)419.3[M+H],Tr=1.89min (LCMS method 2).

Example 13

( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)nicotinecarbonitrile (( E ) -6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile)-compound 13

Step 1: Synthesis of ( E )-3-(4-(2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )-3-(4-(2- chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 13a)

8-Bromo-2-chloroquinazoline (500mg, 2.05mmol, Ark Pharm Inc, AK-27609), Compound 1c (776mg, 2.67mmol), Tripotassium Phosphate (633mg, 3.08mmol) and 1,1'-bis A mixture of (di-tert-butylphosphino)ferrocene palladium dichloride (134 mg, 0.21 mmol) was dissolved in a mixture of N , N -dimethylformamide:water (85:15, 10 mL) under argon ) middle. The reaction was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalents of hexanes were added and the mixture was filtered through a 2 cm layer of silica gel washed with additional hexane/ethyl acetate mixture (1/1). The combined organics were concentrated under reduced pressure and the residue was treated with ether in a sonic bath. The solid product was filtered off and washed twice with ether and once with hexane to provide the title compound 13a . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.70 (s, 1H), 8.30 (dd, J =7.1, 2.5Hz, 1H), 7.99-7.84 (m, 2H), 7.66 (d, J =16.7Hz) ,1H),7.49(s,2H),6.50(d, J =16.7Hz,1H),1.85(s,6H).LCMS(m/z)320.1[M+H],Tr=1.40min (LCMS method 3).

Step 2: Synthesis of ( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)nicotinecarbonitrile (Compound 13)

-4,5-二基)雙(二苯基膦)(93mg,0.16mmol)及醋酸鈀(II)(36mg,0.16mmol)在氬氣下於N-甲基-2-吡咯啶酮(10mL)中結合。將反應在80℃下於密封容器中加熱30分鐘。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥，加入0.5體積當量的己烷並透過以另外己烷/乙酸乙 酯混合物(1/1)清洗的2cm矽膠層過濾此混合物。減壓濃縮結合的有機物。將粗殘餘物在音波浴中以乙醚處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物13。¹H NMR(400MHz,DMSO-d ₆)δ 10.85(s,1H),9.52(s,1H),8.66(dd,J=2.3,0.9Hz,1H),8.10(dd,J=8.0,1.4Hz,1H),7.92(dd,J=8.9,0.9Hz,1H),7.85-7.70(m,2H),7.65(dd,J=8.1,7.1Hz,1H),7.57-7.48(m,3H),6.56(d,J=16.7Hz,1H),1.89(s,6H).LCMS(m/z)403.2[M+H],Tr=1.48min(LCMS方法3)。 Compound 13a (508 mg, 1.60 mmol), 6-amine nicotine carbonitrile (567 mg, 4.77 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (1.64 g, 12.71 mmol) , (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol) and palladium(II) acetate (36 mg, 0.16 mmol) in N-methyl-2-pyrrolidinone (10 mL) under argon ) combined. The reaction was heated in a sealed vessel at 80°C for 30 minutes. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalents of hexanes were added and the mixture was filtered through a 2 cm layer of silica gel washed with additional hexane/ethyl acetate mixture (1/1). The combined organics were concentrated under reduced pressure. The crude residue was treated with ether in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 13 . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.85 (s, 1H), 9.52 (s, 1H), 8.66 (dd, J =2.3, 0.9Hz, 1H), 8.10 (dd, J =8.0, 1.4Hz ,1H),7.92(dd, J =8.9,0.9Hz,1H),7.85-7.70(m,2H),7.65(dd, J =8.1,7.1Hz,1H),7.57-7.48(m,3H), 6.56 (d, J = 16.7 Hz, 1H), 1.89 (s, 6H). LCMS (m/z) 403.2 [M+H], Tr = 1.48 min (LCMS method 3).

Example 14

( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine)nicotinecarbonitrile (( E )-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile)-compound 14

Step 1: Synthesis of (E)-3-(4-(2-Chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile ((E)-3-( 4-(2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 14a)

Compound 1c (100 mg, 0.35 mmol), 8-bromo-2-chloro-6-fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc, AK-93358), 1,1'-bis(di-tert-butyl) phosphino)ferrocene palladium dichloride (50 mg, 0.08 mmol) and potassium phosphate tribasic monohydrate in N,N-dimethylformamide (3 mL) and water (0.3 mL) ) (200 mg, 0.77 mmol) was heated under argon at 80 °C for 30 min. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography (gradient from 0 to 100% ethyl acetate in isohexane) to provide the title compound 14a . LCMS (m/z) 337.9 [M+H], Tr=4.52 min (LCMS method 1).

Step 2: Synthesis of ( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine) Nicotine carbonitrile (compound 14)

-4,5-二基)雙(二苯基膦)(180mg,0.31mmol)及醋酸鈀(II)(40mg,0.18mmol)在氬氣下於N-甲基-2-吡咯啶酮(3mL)中結合。將反應在100℃下於密封容器中加熱1個小時。將反應混合物冷卻至室溫並直接以矽膠層析法(梯度從60至100%之異己烷中的乙酸乙酯及梯度從0至20%之乙酸乙酯中的甲醇)純化以提供標題化合物14。¹H NMR(400MHz,DMSO-d ₆)δ 9.62(s,1H),8.77(dd,J=2.3,0.8Hz,1H),8.08-7.99(m,1H),7.99-7.91(m,1H),7.87(d,J=16.7Hz,1H),7.68(s,2H),7.65-7.60(m,1H),7.60-7.53(m,1H),7.36(d,J=8.2,Hz,1H),6.68(d,J=16.7Hz,1H),2.01(s,6H).LCMS(m/z)420.9[M+H],Tr=4.62min(LCMS方法1)。 Compound 14a (100 mg, 0.30 mmol), 6-aminenicotine carbonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (0.5 mL, 2.86 mmol) , (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (180 mg, 0.31 mmol) and palladium(II) acetate (40 mg, 0.18 mmol) in N-methyl-2-pyrrolidinone (3 mL) under argon ) combined. The reaction was heated at 100°C in a sealed vessel for 1 hour. The reaction mixture was cooled to room temperature and purified directly by silica gel chromatography (gradient from 60 to 100% ethyl acetate in isohexane and gradient from 0 to 20% methanol in ethyl acetate) to provide the title compound 14 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.77 (dd, J =2.3, 0.8 Hz, 1H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H) ,7.87(d, J =16.7Hz,1H),7.68(s,2H),7.65-7.60(m,1H),7.60-7.53(m,1H),7.36(d, J =8.2,Hz,1H) , 6.68(d, J =16.7Hz,1H),2.01(s,6H).LCMS(m/z)420.9[M+H],Tr=4.62min (LCMS method 1).

Example 15

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-2,4 -Dimethylnicotinecarbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4 -dimethylnicotinonitrile)-compound 15

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl) Amine)-2,4-dimethylnicotinecarbonitrile (Compound 15)

-4,5-二基)雙(二苯基膦)(4mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(1mL)中結合。將反應在120℃下於密封容器中加熱4個小時。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥並透過以另外乙酸乙酯清洗的2cm矽膠層過濾此溶液。減壓濃縮結合的有機物。將粗殘餘物在音波浴中以乙醚處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物15。¹H NMR(400MHz,DMSO-d ₆)δ 9.56(bs,1H),9.29(bs,1H),8.44(d,J=8.0Hz,1H),7.99-7.47(m,5H),7.41-7.10(m,1H),6.55(d,J=16.7Hz,1H),2.41(bs,3H),1.96(s,6H),1.62(bs,3H).LCMS(m/z)446.4[M+H],Tr=1.19min(LCMS方法3)。 Compound 2a (20 mg, 0.06 mmol), 6-amino-2,4-dimethylnicotinonitrile (26 mg, 0.18 mmol, Key Organics Ltd, 1X-0933) , N,N-diisopropylethylamine (622mg, 0.48mmol), (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (1 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and the solution filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with ether in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 15 . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.56 (bs, 1H), 9.29 (bs, 1H), 8.44 (d, J = 8.0Hz, 1H), 7.99-7.47 (m, 5H), 7.41-7.10 (m,1H),6.55(d, J =16.7Hz,1H),2.41(bs,3H),1.96(s,6H),1.62(bs,3H).LCMS(m/z)446.4[M+H ],Tr=1.19min (LCMS method 3).

Example 16

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)- 2-Methylnicotinecarbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile )-Compound 16

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-2- Methylnicotine carbonitrile (compound 16)

-4,5-二基)雙(二苯基膦)(4mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(1mL)中結合。將反應在120℃下於密封容器中加熱4個小時。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥並透過以另 外乙酸乙酯清洗的2cm矽膠層過濾此溶液。減壓濃縮結合的有機物。將粗殘餘物在音波浴中以乙醚處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物16。¹H NMR(400MHz,DMSO-d ₆)δ 10.92(s,1H),9.55(s,1H),9.10(s,1H),8.46(dd,J=8.3,1.3Hz,1H),8.19(d,J=2.2Hz,1H),7.89-7.73(m,3H),7.69(s,2H),7.32(d,J=2.2Hz,1H),6.68(d,J=16.7Hz,1H),2.37(s,3H),1.95(s,6H).LCMS(m/z)432.4[M+H],Tr=1.15min(LCMS方法3)。 Compound 2a (20 mg, 0.06 mmol), 6-amino-2-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-78835), N,N- Diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (1 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and the solution filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with ether in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 16 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.92(s, 1H), 9.55(s, 1H), 9.10(s, 1H), 8.46(dd, J =8.3, 1.3Hz, 1H), 8.19(d , J =2.2Hz,1H),7.89-7.73(m,3H),7.69(s,2H),7.32(d, J =2.2Hz,1H),6.68(d, J =16.7Hz,1H),2.37 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr=1.15 min (LCMS method 3).

Example 17

( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-5-methyl Nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile)-compound 17

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-5- Methylnicotine carbonitrile (compound 17)

-4,5-二基)雙(二苯基膦)(4mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(1mL)中結合。將反應在120℃下於密封容器中加熱4個小時。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥並透過以另外乙酸乙酯清洗的2cm矽膠層過濾此溶液。減壓濃縮結合的有機物。將粗殘餘物在音波浴中以乙醚處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物17。¹H NMR(400MHz,DMSO-d ₆)δ 10.92(s,1H),9.55(s,1H),9.10(s,1H),8.46(dd,J=8.3,1.3Hz,1H),8.25-8.13(m,1H),7.91-7.72(m,3H),7.69(s,2H),7.35-7.29(m,1H),6.68(d,J=16.7Hz,1H),2.37(s,3H),1.95(s,6H).LCMS(m/z)432.4[M+H],Tr=1.19min(LCMS方法3)。 Compound 2a (20 mg, 0.06 mmol), 6-amino-5-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-25043), N,N- Diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (1 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and the solution filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with ether in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 17 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.92(s,1H), 9.55(s,1H), 9.10(s,1H), 8.46(dd, J =8.3,1.3Hz,1H), 8.25-8.13 (m, 1H), 7.91-7.72(m, 3H), 7.69(s, 2H), 7.35-7.29(m, 1H), 6.68(d, J = 16.7Hz, 1H), 2.37(s, 3H), 1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr=1.19 min (LCMS method 3).

Example 18

( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-4-methyl nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6- dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile)-compound 18

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)-4- Methylnicotine carbonitrile (compound 18)

-4,5-二基)雙(二苯基膦)(4mg,0.006mmol)及醋酸鈀(II)(1mg,0.006mmol)在氬氣下於N-甲基-2-吡咯啶酮(1mL)中結合。將反應在120℃下於密封容器中加熱4個小時。將反應混合物冷卻至室溫並以水及乙酸乙酯稀釋。將有機層分離並以鹽水清洗兩次，利用硫酸鎂乾燥並透過以另外乙酸乙酯清洗的2cm矽膠層過濾此溶液。減壓濃縮結合的有機物。將粗 殘餘物在音波浴中以乙醚處理5分鐘。將固體化合物濾出並以乙醚清洗兩次及己烷清洗一次以提供標題化合物18。¹H NMR(400MHz,DMSO-d6)δ 11.97(bs,1H),9.55(bs,1H),9.32(bs,1H),8.48-8.37(m,1H),7.90-7.62(m,5H),7.52-7.43(m,1H),7.32-7.23(m,1H),6.69(d,J=16.7Hz,1H),2.45(s,3H),1.96(s,6H).LCMS(m/z)432.3[M+H],Tr=1.25min(LCMS方法3)。 Compound 2a (20 mg, 0.06 mmol), 6-amino-4-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-80125), N,N- Diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) in N-methyl-2-pyrrolidinone (1 mL) under argon ) combined. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and the solution filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with ether in a sonic bath for 5 minutes. The solid compound was filtered off and washed twice with ether and once with hexane to provide the title compound 18 . ¹ H NMR (400MHz, DMSO- d 6) δ 11.97(bs,1H), 9.55(bs,1H), 9.32(bs,1H), 8.48-8.37(m,1H), 7.90-7.62(m,5H) ,7.52-7.43(m,1H),7.32-7.23(m,1H),6.69(d, J =16.7Hz,1H),2.45(s,3H),1.96(s,6H).LCMS(m/z ) 432.3[M+H], Tr=1.25min (LCMS method 3).

Example 19

( E )-4-((4-Amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) Benzonitrile (( E )-4-((4-Amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 19

Step 1: Synthesis of 2-amino-3-bromo-5-chlorobenzoic acid (compound 19a)

A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc, AK-26989) and N,N-dimethylformamide (100 mL) A mixture of N-bromosuccinimide (5.4 g, 30 mmol) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 mL) and the product was extracted with ether (400 mL). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound 19a . LCMS (m/z) 250.0 [M+H], Tr=4.05 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-chloroquinazoline-2,4( 1H , 3H )-dione (8-bromo-6-chloroquinazoline-2,4( 1H , 3H )-dione)( Compound 19b)

Compound 19a (5.3 g, 21 mmol) and urea (30 g, 500 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled, diluted with methanol (100 mL) and the product was filtered off. The solid was washed with water (50 mL) and methanol (50 mL) to provide the title compound 19b . LCMS (m/z) 275.0 [M+H], Tr=3.32 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2,6-dichloroquinazolin-4-amine (compound 19c)

A mixture of compound 19b (5.3 g, 21 mmol), phosphorus(V)oxychloride (15 mL) and N , N -dimethylformamide (3 drops) was heated at 120°C for 14 Hour. The reaction mixture was cooled, poured into water (200 mL) and the product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (50 mL) and stirred at room temperature for 14 hours. The solid product was filtered off to provide the title compound 19c . ¹ H NMR (400 MHz, DMSO- d ₆ )δ 8.65(s, 2H), 8.47(d, J =2.2Hz, 1H), 8.25(d, J =2.2Hz, 1H).LCMS(m/z) 291.9 [M+H], Tr=3.86 min (LCMS method 1).

Step 4: Synthesis of ( E )-3-(4-(4-amine-2,6-dichloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )-3 -(4-(4-amino-2,6-dichloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 19d)

Compound 19c (146 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), tripotassium phosphate monohydrate (230 mg, 1 mmol) and [1,1'-bis(diphenylphosphino) complexed with dichloromethane ) ferrocene]palladium(II) dichloride (65 mg, 0.1 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (10:1, 5.5 mL) under argon and This mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80 to 100% ethyl acetate in isohexane) to provide the title compound 19d . LCMS (m/z) 369.0 [M+H], Tr=4.30 (LCMS method 1).

Step 5: Synthesis of ( E )-4-((4-amine-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazoline-2- base)amine)benzonitrile (compound 19)

-4,5-二基)雙(二苯基膦)(27mg,0.046mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(2mL)中。接著經由注射器將N,N-二異丙基乙基胺(174μL,1mmol)加入並在100℃下將反應混合物攪拌1個小時。藉由矽膠快速層析法(梯度從40至60%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的水中乙腈)再純化以提供標題化合物19。¹H NMR(400MHz,DMSO-d ₆)δ 9.55(s,1H),8.34(d,J=2.3Hz,1H),7.74(d,J=16.7Hz,1H),7.66(d,J=8.9Hz,2H),7.55(d,J=2.3Hz,1H),7.52(s,2H),7.40-7.35(m,2H),7.26(d,J=8.9Hz,2H),6.55(d,J=16.7Hz,1H),1.93(s,6H).LCMS(m/z)451.2[M+H],Tr=4.25min(LCMS方法1)。 Compound 19d (85 mg, 0.23 mmol), 4-aminobenzonitrile (33 mg, 0.28 mmol, Sigma-Aldrich), palladium(II) acetate (10 mg, 0.046 mmol) and (9,9-dimethyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (27 mg, 0.046 mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon. Next, N,N-diisopropylethylamine (174 μL, 1 mmol) was added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel flash chromatography (gradient from 40 to 60% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 to 100% acetonitrile in water) was repurified to provide the title compound 19 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.55(s, 1H), 8.34(d, J =2.3Hz, 1H), 7.74(d, J =16.7Hz, 1H), 7.66(d, J =8.9 Hz, 2H), 7.55(d, J =2.3Hz, 1H), 7.52(s, 2H), 7.40-7.35(m, 2H), 7.26(d, J =8.9Hz, 2H), 6.55(d, J =16.7Hz,1H),1.93(s,6H).LCMS(m/z)451.2[M+H],Tr=4.25min (LCMS method 1).

Example 20

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine) Nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile)-compound 20

Step 1: Synthesis of 2-amino-3-bromo-5-(2-amino-3-bromo-5-fluorobenzoic acid) (compound 20a)

A mixture of 2-amino-5-fluorobenzoic acid (10 g, 65 mmol, Ark Pharm Inc, AK-35193) and N , N -dimethylformamide (100 mL ) A mixture of N -bromosuccinimide (12 g, 67 mmol) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to provide the title compound 20a . LCMS (m/z) 233.7 [M+H], Tr=3.75 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-fluoroquinazoline-2,4( 1H , 3H )-dione (8-bromo-6-fluoroquinazoline-2,4( 1H , 3H )-dione) (Compound 20b)

Compound 20a (12 g, 51 mmol) and urea (20 g, 333 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) to provide the title compound 20b . LCMS(m/z)259.0[M+H],Tr=3.23min(LCMS method 1)

Step 3: Synthesis of 8-bromo-2-chloro-6-fluoroquinazolin-4-amine (compound 20c)

A mixture of compound 20b (3 g, 20 mmol), phosphorus(V) ammonium chloride (20 mL) and N , N -dimethylformamide (3 drops) was heated at 120°C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was evaporated to dryness and the solid residue was suspended in water. The solid product was filtered off to provide the title compound 20c . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.59 (s, 1H), 8.46 (s, 1H), 8.19 (dd, J =8.3, 2.7 Hz, 1H), 8.13 (dd, J =9.2, 2.7 Hz ,1H).LCMS(m/z)275.7[M+H],Tr=3.74min (LCMS method 1).

Step 4: Synthesis of ( E )-3-(4-(4-amine-2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E ) -3-(4-(4-amino-2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 20d)

Compound 20c (276 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), tripotassium phosphate monohydrate (460 mg, 2 mmol) and [1,1'-bis(diphenylphosphino) complexed with dichloromethane A mixture of ferrocene]palladium(II) dichloride (65 mg, 0.1 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (10:1, 11 mL) under argon and this The mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80 to 100% ethyl acetate in isohexane) to provide the title compound 20d . LCMS (m/z) 352.9 [M+H], Tr=4.12 min (LCMS method 1).

Step 5: Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazoline-2- base) amine) nicotine carbonitrile (compound 20)

-4,5-二基)雙(二苯基膦)(58mg,0.1mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(5mL)中。接著經由注射器將N,N-二異丙基乙基胺(348μL,2mmol)加入並在100℃下將反應混合物攪拌1個小時。藉由矽膠層析法(梯度從40至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的帶有0.1%TFA之水中乙腈)再純化以作為TFA鹽提供標題化合物20。¹H NMR(400MHz,DMSO-d ₆)δ 9.56(bs,1H),9.46(bs,1H),8.40-8.20(m,2H),8.02-7.84(m,1H),7.82(d,J=16.6Hz,1H),7.69(s,2H),7.51(bs,1H),7.42(bs,1H),6.69(d,J=16.6Hz,1H),1.98(s,6H).LCMS(m/z)435.8[M+H],Tr=3.45min(LCMS方法1)。 Compound 20d (176 mg, 0.5 mmol), 6-aminenicotine carbonitrile (178 mg, 1.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (22 mg, 0.1 mmol) and (9,9-di Methyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL) under argon. Next, N,N-diisopropylethylamine (348 μL, 2 mmol) was added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel chromatography (gradient from 40 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 Repurification to 100% acetonitrile in water with 0.1% TFA) provided the title compound 20 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.56(bs, 1H), 9.46(bs, 1H), 8.40-8.20(m, 2H), 8.02-7.84(m, 1H), 7.82(d, J = 16.6Hz, 1H), 7.69(s, 2H), 7.51(bs, 1H), 7.42(bs, 1H), 6.69(d, J =16.6Hz, 1H), 1.98(s, 6H).LCMS(m/ z) 435.8 [M+H], Tr=3.45 min (LCMS method 1).

Example 21

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amine ) Nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile)-compound twenty one

Step 1: Synthesis of 2-amino-3-bromo-5-methylbenzoic acid (2-amino-3-bromo-5- methylbenzoic acid) (compound 21a)

Combine 2-amino-5-methylbenzoic acid (10 g, 66 mmol, Ark Pharm, Inc AK-34555) in N,N-dimethylformamide (100 mL) A mixture of N-bromosuccinimide (12 g, 67 mmol) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to provide the title compound 21a . LCMS (m/z) 229.80 [M+H], Tr=3.87 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-methylquinazoline-2,4( 1H , 3H )-dione (8-bromo-6-methylquinazoline-2,4( 1H , 3H )-dione ) (Compound 21b)

Compound 21a (5 g, 22 mmol) and urea (30 g, 500 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to provide the title compound 21b . LCMS (m/z) 254.7 [M+H], Tr=3.19 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-methylquinazolin-4-amine (compound 21c)

A mixture of compound 21b (5 g, 20 mmol), phosphorus(V) ammonium chloride (15 mL) and N , N -dimethylformamide (3 drops) was heated at 120°C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The solid product was filtered off to provide the title compound 21c . ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.41(s, 2H), 8.06(d, J =1.7Hz, 1H), 8.01(d, J =1.7Hz, 1H), 2.42(s, 3H). LCMS (m/z) 271.8 [M+H], Tr=3.65 min (LCMS method 1).

Step 4: Synthesis of ( E )-3-(4-(4-amine-2-chloro-6-methylquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )-3-(4-(4-amino-2-chloro-6-methylquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 21d)

Compound 21c (273 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), tripotassium phosphate monohydrate (460 mg, 2 mmol) and [1,1'-bis(diphenylphosphino) complexed with dichloromethane were combined A mixture of ferrocene]palladium(II) dichloride (65 mg, 0.1 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (10:1, 5.5 mL) under argon and the The reaction mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 40 to 100% ethyl acetate in isohexane) to provide the title compound 21d . LCMS (m/z) 348.9 [M+H], Tr = 4.17 min (LCMS method 1).

Step 5: Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazoline-2 -yl)amine)nicotinecarbonitrile (compound 21)

-4,5-二基)雙(二苯基膦)(58mg,0.1mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(5mL)中。接著經由注射器將N,N-二異丙基乙基胺(435μL,2.5mmol)加入並在110℃下將反應混合物攪拌6個小時。藉由矽膠層析法(梯度從40至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的帶有0.1%TFA之水中乙腈)再純化以作為TFA鹽提供標題化合物21。¹H NMR(400MHz,DMSO-d ₆)δ 9.51(s,1H),9.31(s,1H),8.33-8.24(m,2H),7.82(d,J=16.7Hz,1H),7.77-7.66(m,3H),7.58-7.50(m,1H),7.45-7.36(m,1H),6.69(d,J=16.7Hz,1H),2.54(s,3H),1.96(s,6H).LCMS(m/z)432.0[M+H],Tr=3.56min(LCMS方法1)。 Compound 21d (175 mg, 0.5 mmol), 6-aminenicotine carbonitrile (298 mg, 2.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (23 mg, 0.1 mmol) and (9,9-di Methyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL) under argon. N,N-diisopropylethylamine (435 μL, 2.5 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 6 hours. The product was isolated by silica gel chromatography (gradient from 40 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 Repurification to 100% acetonitrile in water with 0.1% TFA) provided the title compound 21 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.51(s,1H), 9.31(s,1H), 8.33-8.24(m,2H), 7.82(d, J =16.7Hz,1H), 7.77-7.66 (m, 3H), 7.58-7.50(m, 1H), 7.45-7.36(m, 1H), 6.69(d, J = 16.7Hz, 1H), 2.54(s, 3H), 1.96(s, 6H). LCMS (m/z) 432.0 [M+H], Tr=3.56 min (LCMS method 1).

Example 22

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazoline-2- ( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile )-Compound 22

Step 1: Synthesis of 2-amino-3-bromo-5-nitrobenzoic acid (compound 22a)

2-amino-5-nitrobenzoic acid (5 g, 27 mmol, Sigma-Aldrich) and N-bromosuccinic acid in N,N-dimethylformamide (100 mL) A mixture of imide (6 g, 34 mmol) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to provide the title compound 22a . LCMS (m/z) 261.03 [M+H], Tr=3.70 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-nitroquinazoline-2,4( 1H , 3H )-dione (8-bromo-6-nitroquinazoline-2,4( 1H , 3H )-dione) (Compound 22b)

Compound 22a (5 g, 22 mmol) and urea (20 g, 333 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to provide the title compound 22b . LCMS (m/z) 286.2 [M+H], Tr=3.21 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-nitroquinazolin-4-amine (compound 22c)

A mixture of compound 22b (5 g, 17 mmol), phosphorus(V) amide chloride (15 mL) and N , N -dimethylformamide (4 drops) was heated at 120°C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and water was added. The solid product was filtered off to provide the title compound 22c . ¹ H NMR(400MHz, DMSO- d ₆ )δ 9.34(d, J =2.4Hz,1H),8.79(d, J =2.4Hz,1H).LCMS(m/z)303.0[M+H],Tr =3.97min (LCMS method 1).

Step 4: Synthesis of (E)-3-(4-(4-amine-2-chloro-6-nitroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile ((E) -3-(4-(4-amino-2-chloro-6-nitroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 22d)

Compound 22c (152 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), tripotassium phosphate monohydrate (230 mg, 1 mmol) and [1,1'-bis(diphenylphosphino) complexed with dichloromethane ) ferrocene]palladium(II) dichloride (33 mg, 0.05 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (10:1, 5.5 mL) under argon and The reaction mixture was stirred at 80°C for 7 hours. The product was isolated by silica gel chromatography (gradient from 40 to 100% ethyl acetate in isohexane) to provide the title compound 22d . LCMS (m/z) 379.9 [M+H], Tr=4.40 min (LCMS method 1).

Step 5: Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazoline-2- base) amine) nicotine carbonitrile (compound 22)

-4,5-二基)雙(二苯基膦)(34mg,0.06mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(5mL)中。接著經由注射器將N,N-二異丙基乙基胺(514μL,2.95mmol)加入並在100℃下將反應混合物攪拌1個小時。藉由矽膠層析法(梯度從40至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的帶有0.1%TFA之水中乙腈)再純化以作為TFA鹽提供標題化合物22。¹H NMR(400MHz,DMSO-d ₆)δ 9.43(bs,2H),7.80(d,J=16.7Hz,1H),7.77-7.50(m,7H),7.48(bs,1H),6.53(d,J=16.7Hz,1H),1.97(s,6H).LCMS(m/z)463.0[M+H],Tr=3.98min(LCMS方法1)。 Compound 22d (110 mg, 0.29 mmol), 6-aminenicotine carbonitrile (171 mg, 1.45 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (13 mg, 0.06 mmol) and (9,9- Dimethyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (34 mg, 0.06 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL) under argon. Next, N,N-diisopropylethylamine (514 μL, 2.95 mmol) was added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel chromatography (gradient from 40 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 Repurification to 100% acetonitrile in water with 0.1% TFA) provided the title compound 22 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.43(bs, 2H), 7.80(d, J =16.7Hz, 1H), 7.77-7.50(m, 7H), 7.48(bs, 1H), 6.53(d , J =16.7Hz,1H),1.97(s,6H).LCMS(m/z)463.0[M+H],Tr=3.98min (LCMS method 1).

Example 23

( E )-6-((4,6-diamine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)nicotine Base carbonitrile (( E )-6-((4,6-Diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile)-compound 23

Synthesis of ( E )-6-((4,6-diamine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) Nicotine carbonitrile (compound 23)

Compound 22 (20 mg, 0.043 mmol) was dissolved in a methanol-acetic acid mixture (10:1, 2 mL), a portion of iron powder (20 mg, 0.358 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The product was isolated by silica gel chromatography (gradient from 10 to 30% methanol in ethyl acetate) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 to 100% acetonitrile in water with 0.1% TFA) was repurified to provide the title compound 23 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.22(s, 1H), 9.04(s, 1H), 8.26-8, 21(m, 1H), 7.82(d, J =16.6Hz, 1H), 7.83 -7.74(m, 1H), 7.68(s, 2H), 7.51(s, 1H), 7.38-7.32(m, 1H), 7.11(s, 1H), 6.69(d, J = 16.6Hz, 1H), 1.98(s,6H).LCMS(m/z)433.1[M+H], Tr=3.68min (LCMS method 1).

Example 24

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl) Amine) nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile)- Compound 24

Step 1: Synthesis of 2-amino-3-bromo-5-methoxybenzoic acid (compound 24a)

2-amino-5-methoxybenzoic acid (3.95g, 23.6mmol, Sigma-Aldrich) and N in N,N-dimethylformamide (80mL) - A mixture of bromosuccinimide (4.2 g, 23.6 mmol) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 mL) and the solid product was filtered off and washed with water to provide the title compound 24a . LCMS (m/z) 245.8 [M+H], Tr=4.06 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-methoxyquinazoline-2,4( 1H , 3H )-dione (8-bromo-6-methoxyquinazoline-2,4( 1H , 3H )- dione) (compound 24b)

Compound 24a (2.19 g, 8.9 mmol) and urea (12 g, 200 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with water (50 mL) to provide the title compound 24b .

Step 3: Synthesis of 8-bromo-2-chloro-6-methoxyquinazolin-4-amine (compound 24c)

A mixture of compound 24b (2.45 g, 9 mmol), phosphorus(V) ammonium chloride (10 mL) and N , N -dimethylformamide (5 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added. The solid product was filtered off to provide the title compound 24c . LCMS (m/z) 287.7 [M+H], Tr=4.33 min (LCMS method 1).

Step 4: Synthesis of ( E )-3-(4-(4-amine-2-chloro-6-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile ((( E )-3-(4-(4-amino-2-chloro-6-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 24d)

Compound 24c (30 mg, 0.1 mmol), compound 1c (34 mg, 0.12 mmol), tripotassium phosphate monohydrate (46 mg, 0.2 mmol) and [1,1'-bis(diphenylphosphine) complexed with dichloromethane A mixture of N , N -dimethylformamide and water (10:1, 2 mL) was dissolved under argon The reaction mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) to provide the title compound 24d . LCMS (m/z) 364.9 [M+H], Tr=4.65 min (LCMS method 1).

Step 5: Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazoline- 2-yl)amine)nicotinecarbonitrile (compound 24)

-4,5-二基)雙(二苯基膦)(10mg,0.016mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(1mL)中。接著經由注射器將N,N-二異丙基乙基胺(37μL,0.21mmol)加入並在100℃下將反應混合物攪拌2個小時。藉由矽膠層析法(梯度從60至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的帶有0.1%TFA之水中乙腈)再純化以作為TFA鹽提供標題化合物24。¹H NMR(400MHz,DMSO-d ₆)δ 13.52(bs,1H),11.99(bs,1H), 9.46(bs,1H),9.26(bs,1H),8.28(s,1H),7.97(s,1H),7.83(d,J=16.7Hz,1H),7.70(s,2H),7.62-7.48(m,2H),7.42-7.36(m,1H),6.69(d,J=16.7Hz,1H),3.95(s,3H),1.98(s,6H).LCMS(m/z)448.0[M+H],Tr=3.95min(LCMS方法1)。 Compound 24d (15 mg, 0.041 mmol), 6-aminenicotine carbonitrile (24 mg, 0.21 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (4 mg, 0.016 mmol) and (9,9-di Methyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (10 mg, 0.016 mmol) was dissolved in N-methyl-2-pyrrolidone (1 mL) under argon. Next, N,N-diisopropylethylamine (37 μL, 0.21 mmol) was added via syringe and the reaction mixture was stirred at 100° C. for 2 hours. The product was isolated by silica gel chromatography (gradient from 60 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 Repurification to 100% acetonitrile in water with 0.1% TFA) provided the title compound 24 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 13.52(bs, 1H), 11.99(bs, 1H), 9.46(bs, 1H), 9.26(bs, 1H), 8.28(s, 1H), 7.97(s ,1H),7.83(d, J =16.7Hz,1H),7.70(s,2H),7.62-7.48(m,2H),7.42-7.36(m,1H),6.69(d, J =16.7Hz, 1H), 3.95 (s, 3H), 1.98 (s, 6H). LCMS (m/z) 448.0 [M+H], Tr=3.95 min (LCMS method 1).

Example 25

( E )-4-((4-Amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amine) Benzonitrile (( E )-4-((4-Amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 25

Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzoic acid (compound 25a)

Combine 2-amino-5-bromobenzoic acid (1 g, 4.6 mmol, Sigma-Aldrich) and N-iodine in N,N-dimethylformamide (30 mL) A mixture of N -iodosuccinimide (1.9 g, 8.4 mmol) was stirred at room temperature for 48 hours. The reaction mixture was poured into water (100 mL). The solid product was filtered off and washed with water to provide the title compound 25a . LCMS (m/z) 341.9 [M+H], Tr=4.53 min (LCMS method 1).

Step 2: Synthesis of 6-bromo-8-iodoquinazoline-2,4( 1H , 3H )-dione (6-bromo-8-iodoquinazoline-2,4( 1H , 3H )-dione) (Compound 25b)

Compound 25a (1.2 g, 3.5 mmol) and urea (10 g, 166 mmol) were heated at 200 °C for 3 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to provide the title compound 25b .

Step 3: Synthesis of 6-bromo-2-chloro-8-iodoquinazolin-4-amine (compound 25c)

A mixture of compound 25b (5.33 g, 14.5 mmol), phosphorus(V) amide chloride (30 mL) and N , N -dimethylformamide (3 drops) was heated at 120°C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and treated with silica gel column chromatography (gradient from 10 to 50% ethyl acetate in isohexane) to provide the title compound 25c . ¹ H NMR(400MHz, DMSO- d 6)δ 7.97(d, J =2.4Hz,1H),7.86(d, J =2.4Hz,1H),6.78(bs,2H).LCMS(m/z)383.9 [M+H], Tr=5.98 min (LCMS method 1).

Step 4: Synthesis of ( E )-3-(4-(4-amine-6-bromo-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl) Acrylonitrile (( E )-3-(4-(4-amino-6-bromo-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 25d)

Compound 25c (120 mg, 0.31 mmol), compound 1c (106 mg, 0.37 mmol), tripotassium phosphate monohydrate (143 mg, 0.62 mmol) and [1,1'-bis(diphenylphosphine) complexed with dichloromethane were combined A mixture of N , N -dimethylformamide and water (10:1, 3 mL) was dissolved under argon The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of saturated ammonium chloride and the product was isolated by silica gel chromatography (gradient from 30 to 60% ethyl acetate in isohexane) to provide the title compound 25d . LCMS(m/z)412.8[M+H],Tr=4.62min(LCMS method 1)

Step 5: Synthesis of ( E )-4-((4-amine-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazoline-2- base) amine) benzonitrile (compound 25)

A mixture of compound 25d (55 mg, 0.13 mmol) and 4-aminobenzonitrile (20 mg, 0.17 mmol, Sigma-Aldrich) in isopropanol (2 mL) was heated at 170 °C for 30 min under microwave conditions. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (gradient from 0 to 100% ethyl acetate in isohexane) to provide the title compound 25 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.57(s, 1H), 8.47(d, J =2.2Hz, 1H), 7.75(d, J =16.7Hz, 1H), 7.68-7.63(m, 3H) ),7.52(s,2H),7.32-7.21(m,2H),6.56(d, J =16.7Hz,1H),1.92(s,6H).LCMS(m/z)495.1[M+H], Tr=4.58 min (LCMS method 1).

Example 26

-2-甲腈((E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2-carbonitrile)-化合物26 ( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine) pyridine

-2-Carbononitrile (( E )-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2- carbonitrile) - compound 26

-2-甲腈(化合物26) Synthesis of ( E )-5-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine ) pyridine

-2-carbonitrile (compound 26)

-2-甲腈(5-aminopyrazine-2-carbonitrile)(60mg,0.50mmol,Ark Pharm Inc,AK-21935)、N,N-二異丙基乙基胺(174μL,1.0mmol)、(9,9-二甲基-9H-

-4,5-二基)雙(二苯基膦)(24mg,0.042mmol)及醋酸鈀(II)(9mg,0.042mmol)在氬氣下於N-甲基-2-吡咯啶酮(2mL)中結合。將反應在100℃下於密封容器中加熱7個小時。將反應混合物冷卻至室溫，藉由矽膠層析法(梯度從50至100%之異己烷中的乙酸乙酯)純化並接著藉由逆相層析法(梯度從5至100%的帶有0.1%三氟乙酸之水中乙腈)再純化以提供標題化合物26的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 9.10(s,1H),8.20(s,1H),7.74(d,J=16.7Hz,1H),7.77-7.60(m,2H),7.57(s,2H),6.56 (d,J=16.7Hz,1H),1.94(s,6H).LCMS(m/z)436.9[M+H],Tr=3.59min(LCMS方法1)。 Compound 20d (92 mg, 0.21 mmol), 5-aminopyridine

-2-carbonitrile (5-aminopyrazine-2-carbonitrile) (60 mg, 0.50 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (174 μL, 1.0 mmol), (9, 9-Dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium(II) acetate (9 mg, 0.042 mmol) in N-methyl-2-pyrrolidinone (2 mL) under argon ) combined. The reaction was heated at 100°C in a sealed vessel for 7 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then by reverse phase chromatography (gradient from 5 to 100% with 0.1% trifluoroacetic acid in water (acetonitrile) was repurified to provide the title compound 26 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.10(s, 1H), 8.20(s, 1H), 7.74(d, J =16.7Hz, 1H), 7.77-7.60(m, 2H), 7.57(s) , 2H), 6.56 (d, J = 16.7 Hz, 1H), 1.94 (s, 6H). LCMS (m/z) 436.9 [M+H], Tr=3.59 min (LCMS method 1).

Example 27

-3-甲腈((E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile)-化合物27 ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine) despair

-3-Carbononitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3- carbonitrile) - compound 27

-3-甲腈(化合物27) Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amine )despair

-3-carbonitrile (compound 27)

-3-甲腈(6-aminopyridazine-3-carbonitrile)(60mg,0.50mmol,Matrix Scientific,112287)、N,N-二異丙基乙基胺(174μL,1.0mmol)、(9,9-二甲基-9H-

-4,5-二基)雙(二苯基膦)(24mg,0.042mmol)及醋酸鈀(II)(9mg,0.042mmol)在氬氣下於N-甲基-2-吡咯啶酮(2mL)中結合。將反應在100℃下於密封容器中加熱7個小時。將反應混合物冷卻至室溫，藉由矽膠層析法(梯度從50至100%之異己烷中的乙酸乙酯)純化並接著藉由逆相層析法(梯度從5至100%的帶有0.1%三氟乙酸之水中乙腈)再純化以提供標題化合物27的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 8.18(bs,1H),8.06(bs,1H),7.73(d,J=16.7Hz,1H),7.71-7.58(m,2H),7.54(s,2H),6.55(d,J=16.7Hz,1H),1.93(s,6H).LCMS(m/z)436.9[M+H],Tr=3.73min(LCMS方法1)。 Compound 20d (92 mg, 0.21 mmol), 6-amine

-3-carbonitrile (6-aminopyridazine-3-carbonitrile) (60 mg, 0.50 mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine (174 μL, 1.0 mmol), (9,9-diisopropylethylamine) Methyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium(II) acetate (9 mg, 0.042 mmol) in N-methyl-2-pyrrolidinone (2 mL) under argon ) combined. The reaction was heated at 100°C in a sealed vessel for 7 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then by reverse phase chromatography (gradient from 5 to 100% with 0.1% trifluoroacetic acid in water (acetonitrile) was repurified to provide the title compound 27 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.18(bs, 1H), 8.06(bs, 1H), 7.73(d, J =16.7Hz, 1H), 7.71-7.58(m, 2H), 7.54(s) , 2H), 6.55 (d, J =16.7 Hz, 1H), 1.93 (s, 6H). LCMS (m/z) 436.9 [M+H], Tr=3.73 min (LCMS method 1).

Example 28

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl) Amine)benzonitrile (( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile)-Compound 28

Step 1: Synthesis of 8-bromo-5-methoxyquinazoline-2,4( 1H , 3H )-dione (8-bromo-5-methoxyquinazoline-2,4( 1H , 3H )- dione) (compound 28a)

The mixture of 2-amino-3-bromo-6-methoxybenzoic acid (2-amino-3-bromo-6-methoxybenzoic acid) (2g, 8.1mmol, Ark Pharm Inc, AK137474) and urea (12g, 200mmol) Heated at 200°C for 2 hours. The reaction mixture was cooled and diluted with water (100 mL). The solid product was filtered off and washed with water (50 mL) to provide the title compound 28a .

Step 2: Synthesis of 8-bromo-2-chloro-5-methoxyquinazolin-4-amine (compound 28b)

A mixture of compound 28a (4.67 g, 17 mmol), phosphorus(V) amide chloride (20 mL) and N , N -dimethylformamide (3 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled, poured into an ice-water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic ammonia solution (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the solid residue was extracted with acetone. The acetone solution was concentrated under reduced pressure to provide the title compound 28b . ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.66(s, 1H), 8.26(s, 1H), 8.02(d, J =8.7Hz, 1H), 6.95(d, J =8.7Hz, 1H), 3.98(s,3H).LCMS(m/z) 288.1[M+H], Tr=3.74min (LCMS method 1).

Step 3: Synthesis of ( E )-3-(4-(4-amine-2-chloro-5-methoxyquinazolin-8-yl)-3,5-dimethyl Phenyl)acrylonitrile (( E )-3-(4-(4-amino-2-chloro-5-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 28c)

Compound 28b (100 mg, 0.35 mmol), compound 1c (118 mg, 0.42 mmol)), tripotassium phosphate monohydrate (159 mg, 0.69 mmol) and [1,1'-bis(diphenyl) complexed with dichloromethane were combined A mixture of phosphino)ferrocene]palladium(II) dichloride (23 mg, 0.035 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (10:1,5 mL) under argon The reaction mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 60 to 100% ethyl acetate in isohexane) to provide the title compound 28c . LCMS (m/z) 364.9 [M+H], Tr=4.38 min (LCMS method 1).

Step 4: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazoline- 2-yl)amine)benzonitrile (compound 28)

-4,5-二基)雙(二苯基膦)(12mg,0.02mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(2mL)中。接著經由注射器將N,N-二異丙基乙基胺(87μL,0.5mmol)加入並在110℃下將反應混合物攪拌6個小時。藉由矽膠層析法(梯度從50至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從5至100%的帶有0.1%TFA之水中乙腈)再純化以作為TFA鹽提供標題化合物28。¹H NMR(400MHz,DMSO-d ₆)δ 7.90-7.65(m,3H),7.71(d,J=16.7Hz,1H),7.58-7.45(m,4H),7.07(s,1H),6.55(d,J=16.7Hz,1H),4.07(s,3H),1.95(s,6H).LCMS(m/z)447.0[M+H],Tr=3.85min(LCMS方法1)。 Compound 28c (37 mg, 0.1 mmol), 4-aminobenzonitrile (60 mg, 0.5 mmol, Sigma-Aldrich), palladium(II) acetate (4 mg, 0.02 mmol) and (9,9-dimethyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02 mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon. Next, N,N-diisopropylethylamine (87 μL, 0.5 mmol) was added via syringe and the reaction mixture was stirred at 110° C. for 6 hours. The product was isolated by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 5 Repurification to 100% acetonitrile in water with 0.1% TFA) provided the title compound 28 as the TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.90-7.65 (m, 3H), 7.71 (d, J = 16.7 Hz, 1H), 7.58-7.45 (m, 4H), 7.07 (s, 1H), 6.55 (d, J = 16.7 Hz, 1H), 4.07 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 447.0 [M+H], Tr = 3.85 min (LCMS method 1).

Example 29

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl) Amine) nicotine carbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile)- Compound 29

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl ) amine) nicotine carbonitrile (compound 29)

-4,5-二基)雙(二苯基膦)(12mg,0.02mmol)及醋酸鈀(II)(4mg,0.02mmol)在氬氣下於N-甲基-2-吡咯啶酮(2mL)中結合。將反應在110℃下於密封容器中加熱6個小時。將反應混合物冷卻至室溫，藉由矽膠層析法(梯度從50至100%之異己烷中的乙酸乙酯)純化並接著藉由逆相層析法(梯度從5至100%的帶有0.1%三氟乙酸之水中乙腈)再純化以提供標題化合物29的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 13.31(bs,1H),11.92(bs,1H),9.49(s,1H),9.09(s,1H),8.27(d,J=8.4Hz,1H),7.82(d,J=16.7Hz,1H),7.77(d,J=9.2Hz, 1H),7.68(s,2H),7.55-7.40(m,2H),7.30(d,J=8.4Hz,1H),6.69(d,J=16.7Hz,1H),4.13(s,3H),1.97(s,6H).LCMS(m/z)448.0[M+H],Tr=3.60min(LCMS方法1)。 Compound 28c (37 mg, 0.1 mmol), 6-amine nicotine carbonitrile (60 mg, 0.5 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (87 μL, 0.5 mmol), ( 9,9-Dimethyl-9H-

-4,5-Diyl)bis(diphenylphosphine) (12 mg, 0.02 mmol) and palladium(II) acetate (4 mg, 0.02 mmol) in N-methyl-2-pyrrolidinone (2 mL) under argon ) combined. The reaction was heated in a sealed vessel at 110°C for 6 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then by reverse phase chromatography (gradient from 5 to 100% with 0.1% trifluoroacetic acid in water (acetonitrile) was repurified to provide the title compound 29 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 13.31(bs,1H), 11.92(bs,1H), 9.49(s,1H), 9.09(s,1H), 8.27(d, J =8.4Hz,1H ), 7.82(d, J =16.7Hz, 1H), 7.77(d, J =9.2Hz, 1H), 7.68(s, 2H), 7.55-7.40(m, 2H), 7.30(d, J =8.4Hz ,1H),6.69(d, J =16.7Hz,1H),4.13(s,3H),1.97(s,6H).LCMS(m/z)448.0[M+H],Tr=3.60min(LCMS method 1).

Example 30

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamine)quinazolin-2-yl)amine)benzyl Nitrile (( E )-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile)-Compound 30

Step 1: Synthesis of 8-bromo-2-chloro- N - methylquinazolin-4-amine (compound 30a)

8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) was dissolved in 20% methylamine solution in 6 mL ethanol and the reaction was stirred at room temperature for 15 minutes. The volatiles were removed under reduced pressure and the solid residue was suspended in water. The solid product was filtered off and washed with water (3 x 5 mL) and pentane (3 x 5 mL) to give the title compound 30a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.96(d, J =4.7Hz, 1H), 8.19(dd, J =8.3Hz, J =1.2Hz, 1H), 8.11(dd, J =7.7Hz, J = 1.2Hz, 1H), 7.42(t, J =7.9Hz, 1H), 3.00(d, J =4.3Hz, 3H). HRMS: Calculated (ESI+ for C ₉ H ₈ N ₃ BrCl[M+H] ) is 271.9585, and the measured value is 271.9585. LCMS (m/z) 272.0 [M+H], Tr 3.80 min (LCMS method 1).

Step 2: Synthesis of ( E )-3-(4-(2-chloro-4-(methylamine)quinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )- 3-(4-(2-chloro-4-(methylamino)quinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 30b)

Compound 30a (110 mg, 0.4 mmol), compound 1c (147 mg, 0.52 mmol), tripotassium phosphate monohydrate (138 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphine) complexed with dichloromethane were combined (26 mg, 0.04 mmol) was dissolved in a mixture of N , N -dimethylformamide and water (85:15, 5 mL) under argon and The reaction mixture was stirred at 80°C for 20 minutes. The reaction mixture was concentrated under reduced pressure and the product was isolated by silica gel chromatography (gradient from 50 to 80% ethyl acetate in isohexane) to provide the title compound 30b . ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.88(d, J =4.4Hz, 1H), 8.25(dd, J =8.2Hz, J =1.5Hz, 1H), 7.67-7.58(m, 2H), 7.53(dd, J =7.2Hz, J =1.5Hz,1H),7.43(s,2H),6.46(d, J =16.7Hz,1H),3.01(d, J =4.4Hz,3H),1.85( s,6H).HRMS: Calculated (ESI+) for C20H18N4Cl [ _{M +} H] _349.1215 , found 349.1216. LCMS (m/z) 349.1 [M+H], Tr 4.51 min (LCMS method 1).

Step 3: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamine)quinazolin)amine)benzyl Nitrile (( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile) (Compound 30)

-4,5-二基)雙(二苯基膦)(40mg,0.064mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(3mL)中。接著經由注射器將N,N-二異丙基乙基胺(150μL,0.85mmol)加入並在110℃下將反應混合物攪拌6個小時。將反應混合物減壓濃縮並藉由矽膠層析法(梯度從80至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從0至100%的水中乙腈)再純化以提供標題化合物30。¹H NMR(400MHz,DMSO-d ₆)δ 9.54(s,1H),8.31(d,J=4.3Hz,1H),8.11(d,J=8.4Hz,1H),7.77-7.70(m,3H),7.51(s,2H),7.46(d,J=7.5Hz,1H),7.35(t,J=7.7Hz,1H),7.27(d,J=8.8Hz,2H),6.54(d,J=16.7Hz,1H),3.06(d,J=4.3Hz,3H),1.90(s,6H).HRMS：計 算C₂₇H₂₃N₆[M+H]的(ESI+)為431.1979，實測為431.1977。LCMS(m/z)431.2[M+H],Tr 3.67min(LCMS方法1)。 Compound 30b (52 mg, 0.15 mmol), 4-aminobenzonitrile (90 mg, 0.75 mmol, Sigma-Aldrich), palladium(II) acetate (20 mg, 0.064 mmol) and (9,9-dimethyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. N,N-diisopropylethylamine (150 μL, 0.85 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prep. Packed column, gradient from 0 to 100% acetonitrile in water) was repurified to provide the title compound 30 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.54(s, 1H), 8.31(d, J =4.3Hz, 1H), 8.11(d, J =8.4Hz, 1H), 7.77-7.70(m, 3H) ), 7.51(s, 2H), 7.46(d, J =7.5Hz, 1H), 7.35(t, J =7.7Hz, 1H), 7.27(d, J =8.8Hz, 2H), 6.54(d, J =16.7Hz,1H),3.06(d, J =4.3Hz,3H),1.90(s,6H).HRMS: Calculated (ESI+) of C ₂₇ H ₂₃ N ₆ [M+H] is 431.1979, found 431.1977 . LCMS (m/z) 431.2 [M+H], Tr 3.67 min (LCMS method 1).

Example 31

( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamine)quinazolin-2-yl)amine)nicotine Base carbonitrile (( E )-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile)-compound 31

Synthesis of ( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamine)quinazolin-2-yl)amine) Nicotine carbonitrile (compound 31)

-4,5-二基)雙(二苯基膦)(40mg,0.064mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(3mL)中。接著經由注 射器將N,N-二異丙基乙基胺(150μL,0.85mmol)加入並在110℃下將反應混合物攪拌4個小時。將反應混合物減壓濃縮並藉由矽膠層析法(梯度從80至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從0至100%的帶有0.1%三氟乙酸之水中乙腈)再純化以提供標題化合物31的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 13.53(s,1H),12.28(s,1H),10.13(s,1H),8.41(d,J=8.4Hz,1H),8.29(d,J=8.8Hz,1H),7.88-7.80(m,2H),7.80-7.72(m,1H),7.71(s,2H),7.59-7.49(m,1H),7.46-7.41(m,1H),6.70(d,J=16.7Hz,1H),3.21(d,J=4.4Hz,3H),1.96(s,6H).HRMS：計算C₂₆H₂₂N₇[M+H]的(ESI+)為432.1931，實測為432.1929。LCMS(m/z)432.2[M+H],Tr 3.53min(LCMS方法1)。 Compound 30b (52 mg, 0.15 mmol), 6-aminenicotine carbonitrile (90 mg, 0.75 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg, 0.064 mmol) and (9,9-di Methyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. Next, N,N-diisopropylethylamine (150 μL, 0.85 mmol) was added via syringe and the reaction mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prep. A packed column, gradient from 0 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) was repurified to provide the title compound 31 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 13.53(s, 1H), 12.28(s, 1H), 10.13(s, 1H), 8.41(d, J =8.4Hz, 1H), 8.29(d, J =8.8Hz,1H),7.88-7.80(m,2H),7.80-7.72(m,1H),7.71(s,2H),7.59-7.49(m,1H),7.46-7.41(m,1H), 6.70(d, J =16.7Hz, 1H), 3.21(d, J =4.4Hz, 3H), 1.96(s, 6H).HRMS: Calculate the (ESI+) of C ₂₆ H ₂₂ N ₇ [M+H] as 432.1931, the measured value is 432.1929. LCMS (m/z) 432.2 [M+H], Tr 3.53 min (LCMS method 1).

Example 32

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amine)benzonitrile ( ( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile)-compound 32

Step 1: Synthesis of 4-((4-amino-8-(trimethylstannyl)quinazolin-2-yl)amine)benzonitrile (4-((4-amino-8-(trimethylstannyl)quinazolin- 2-yl)amino)benzonitrile) (compound 32a)

Hexamethylditin (1 mL, 4.82 mmol) was added under argon to 8a (1000 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) in dry dioxane (5 mL) (tetrakis(triphenylphosphine)palladium(0)) (200 mg, 0.17 mmol). The reaction mixture was heated to 100 °C under argon for 14 hours, then cooled to room temperature and purified directly by silica gel chromatography (gradient from 25 to 50% ethyl acetate in isohexane) to provide the title compound 32a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.42(s, 1H), 8.08-8.18(m, 3H), 7.73(d, J =9.9Hz, 1H), 7.64(d, J =8.9Hz, 2H ), 7.51 (bs, 2H), 7.20-7.28 (m, 1H), 0.36 (s, 9H). LCMS (m/z) 424.0 [MH], Tr=4.84 min (LCMS method 1).

Step 2: Synthesis of ( E )-3-(4-bromo-3,5-dimethoxyphenyl)acrylonitrile (( E )-3-(4-bromo-3,5-dimethoxyphenyl)acrylonitrile) (compound 32b)

Potassium t-butoxide (12.3 g, 110 mmol) was slowly added to 4-bromo-3,5-dimethoxybenzaldehyde (4-bromo-3,5- dimethoxybenzaldehyde) (24.5 g, 100 mmol, Ark Pharm Inc., AK-34641) and diethylcyanomethyl phosphonate in anhydrous 2-methyltetrahydrofuran (400 mL) ( 18.6 g, 105 mmol) in solution. The reaction mixture was vigorously stirred at 0°C for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over _MgSO4 and filtered through a 3 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the solid residue was treated with a hexane/diethyl ether mixture (1/3) in a sonic bath for 3 minutes. The solid product was filtered off and washed with hexanes to provide the title compound 32b . ¹ H NMR (400MHz, DMSO- d ₆ )δ 7.61(d, J =16.7Hz, 1H), 7.06(s, 2H), 6.65(d, J =16.7Hz, 1H), 3.87(s, 6H). No MS signal by LCMS (m/z), Tr 2.50 min (LCMS method 2).

Step 3: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amine ) benzonitrile (compound 32)

Compound 32a (20 mg, 0.047 mmol), compound 32b (20 mg, 0.075 mmol) and bis( tritertbutylphosphino )palladium(0)( 20 mg, 0.039 mmol) of the mixture was heated at 100 °C for 2 hours under argon. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column). , a gradient from 0 to 100% acetonitrile in water with 0.1% TFA) was repurified to provide the title compound 32 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.53 (bs, 1H), 9.72-9.53 (m, 2H), 7.88-7.83 (m, 2H), 7.77 (d, J = 16.7Hz, 1H), 7.71 (d, J = 7.8Hz, 2H), 7.58(bs, 1H), 7.54(bs, 1H), 7.41-7.34(m, 1H), 7.16(s, 2H), 6.76(d, J = 16.7Hz, 1H), 3.72 (s, 6H). LCMS (m/z) 449.0 [M+H], Tr=3.48 min (LCMS method 1).

Example 33

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amine)benzonitrile (( E )- 4-((8-(4-(2-Cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile)-Compound 33

Step 1: Synthesis of 4-((8-(trimethylstannyl)quinazolin-2-yl)amine)benzonitrile (4-((8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile) (Compound 33a)

Hexamethylditin (1 mL, 4.82 mmol) was added under argon to 1a (1000 mg, 3.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (200 mg) in dry dioxane (5 mL) , 0.17 mmol) in the mixture. The reaction mixture was heated to 110 °C under argon for 4 hours, then cooled to room temperature and purified directly by silica gel chromatography (gradient from 0 to 30% ethyl acetate in isohexane) to provide the title compound 33a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.53(s,1H), 9.47(s,1H), 8.34(d, J =8.8Hz,1H), 8.31-8.24(m,2H), 8.09-8.02 (m,1H),7.90-7.85(m,2H),7.60-7.51(m,1H),0.05(s,9H).LCMS(m/z)409.0[M+H],Tr=5.54min(LCMS method 1).

Step 2: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amine)benzonitrile ( Compound 33)

Compound 33a (20 mg, 0.048 mmol), compound 32b (20 mg, 0.075 mmol) and bis( tritertbutylphosphino )palladium(0)( 20 mg, 0.039 mmol) of the mixture was heated at 100 °C for 2 hours under argon. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column). , a gradient from 0 to 100% acetonitrile in water with 0.1% TFA) was repurified to provide the title compound 33 as the TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 9.40 (s, 1H), 7.96 (dd, J = 8.1, 1.4 Hz, 1H), 7.78-7.85 (m, 3H), 7.71 (dd, J =7.2,1.4Hz,1H),7.44-7.54(m,3H),7.21(s,2H),6.77(d, J =16.7Hz,1H),3.62(s,6H).LCMS( m/z) 433.98[M+H], Tr=4.39min (LCMS method 1)

Example 34

( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-2- ( E )-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino )nicotinonitrile)-Compound 34

Step 1: Synthesis of 8-bromo-2-chloroquinazolin-4( 3H )-one (8-bromo-2-chloroquinazolin-4( 3H )-one) (compound 34a)

Aqueous sodium hydroxide (30 mL, 0.2 M, 6 mmol) was added to a solution of 8-bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was acidified to pH=5 with glacial acetic acid and concentrated under reduced pressure. Water was added and the solid product was filtered off and washed with water (3 x 20ml) to provide the title compound 34a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 13.51(s, 1H), 8.15(d, J =7.8Hz, 1H), 8.09(d, J =7.8Hz, 1H), 7.42-7.51(m, 1H) ).HRMS: Calculated (ESI+) of C ₈ H ₄ ON ₂ BrClNa[M+Na] was 280.9088, found 280.9089. LCMS (m/z) 259.0 [M+H], Tr 3.58 min (LCMS method 1).

Step 2: Synthesis of ( E )-3-(4-(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (( E )-3-(4-(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile) (Compound 34b)

Compound 34a (74 mg, 0.28 mmol), compound 1c (120 mg, 0.42 mmol), tripotassium phosphate monohydrate (200 mg, 0.87 mmol) and [1,1'-bis(diphenylphosphine) complexed with dichloromethane were combined A mixture of N , N -dimethylformamide and water (10:1, 3.3 mL) under argon The reaction mixture was stirred at 80°C for 2 hours. The product was isolated by silica gel chromatography (gradient from 0 to 100% ethyl acetate in isohexane) to provide the title compound 34b . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.30 (bs, 1H), 8.16 (dd, J =7.7, 1.8 Hz, 1H), 7.67-7.51 (m, 3H), 7.43 (s, 2H), 6.46 (d, J = 16.7 Hz, 1H), 1.88 (s, 6H). LCMS (m/z) 336.1 [M+H], Tr = 4.24 (LCMS method 1).

Step 3: Synthesis of ( E )-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo- 3,4-Dihydroquinazolin-2-yl)amine)nicotinecarbonitrile (Compound 34)

-4,5-二基)雙(二苯基膦)(100mg,0.17mmol)的混合物在氬氣下溶於N-甲基-2-吡咯啶酮(3mL)中。接著經由注射器將N,N-二異丙基乙基胺(1mL,5.7mmol)加入並在100℃下將反應混合物攪拌1個小時。藉由矽膠層析法(梯度從0至100%之異己烷中的乙酸乙酯)將產物分離並接著藉由逆相快速層析法(5.5g C-18 RediSep預填管柱，梯度從0至100%的帶有0.1%三氟乙酸之水中乙腈)再純化以提供標題化合物34的TFA鹽。¹H NMR(400MHz,DMSO-d ₆)δ 12.16(bs,1H),10.26(bs,1H),8.74(bs,1H),8.10(dd,J=7.8,1.6Hz,1H),7.94-7.81(m,1H),7.69(d,J=16.7Hz,1H),7.59-7.36(m,5H),6.51(d,J=16.7Hz,1H),1.94(s,6H).LCMS(m/z)418.9[M+H],Tr=4.11min(LCMS方法1)。 Compound 34b (80 mg, 0.24 mmol), 6-aminenicotine carbonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), palladium (II) acetate (20 mg, 0.09 mmol) and (9,9-di Methyl-9H-

A mixture of -4,5-diyl)bis(diphenylphosphine) (100 mg, 0.17 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. Next, N,N-diisopropylethylamine (1 mL, 5.7 mmol) was added via syringe and the reaction mixture was stirred at 100 °C for 1 hour. The product was isolated by silica gel chromatography (gradient from 0 to 100% ethyl acetate in isohexane) and then by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient from 0 Repurification to 100% acetonitrile in water with 0.1% trifluoroacetic acid) provided the title compound 34 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.16 (bs, 1H), 10.26 (bs, 1H), 8.74 (bs, 1H), 8.10 (dd, J =7.8, 1.6Hz, 1H), 7.94-7.81 (m,1H),7.69(d, J =16.7Hz,1H),7.59-7.36(m,5H),6.51(d, J =16.7Hz,1H),1.94(s,6H).LCMS(m/ z) 418.9 [M+H], Tr=4.11 min (LCMS method 1).

Example 35

( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amine)benzonitrile ((( E )-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6- diethylphenyl)quinazolin-2-yl)amino)benzonitrile)-compound 35

Step 1: Synthesis of ( E )-3-(4-bromo-3,5-diethylphenyl)acrylonitrile (( E )-3-(4-bromo-3,5-diethylphenyl)acrylonitrile) (Compound 35a )

Palladium(II) acetate (224 mg, 1 mmol), acrylonitrile (1060 mg, 20 mmol), tris(o-toluene)phosphine (913 mg, 3 mmol) and triethylamine (4 mL, 30 mmol) were added to a solution of 2 in dry acetonitrile (25 mL). , 5-dibromo-1,3-diethylbenzene (2,5-dibromo-1,3-diethylbenzene) (2920 mg, 10 mmol, Oakwood Products, Inc.-034265), then the mixture was flushed with argon and Heated at 70°C for 3 hours. The reaction mixture was filtered through celite and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and dehydrated and redissolved in ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. Silica gel chromatography (gradient from 0 to 20% ethyl acetate in isohexane) provided the title compound 35a . ¹ H NMR (400MHz, CDCl ₃ )δ 7.31(d, J =16.6Hz, 1H), 7.12(s, 2H), 5.86(d, J =16.6Hz, 1H), 2.79(q, J =7.5Hz, 4H), 1.22 (t, J =7.5Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07min (LCMS method 2).

Step 2: Synthesis of ( E )-3-(3,5-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-diboran-2-yl)phenyl ) Acrylonitrile (( E )-3-(3,5-diethyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile) (Compound 35b)

Compound 35a (300 mg, 1.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diborane ) (432 mg, 1.70 mmol), potassium carbonate (471 mg, 3.4 mmol), palladium(II) acetate (13 mg, 0.06 mmol) and dicyclohexyl ( A mixture of 2',6'-dimethoxy-[1,1'-diphenyl]-2-yl)phosphine (SPhos, 58 mg, 0.14 mmol) was flushed with argon and heated at 100 °C for 2 hours . The reaction mixture was filtered through celite and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and dehydrated and redissolved in ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was re-extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude residue and purified by silica gel chromatography (gradient from 0 to 15% ethyl acetate in isohexane) to provide the title compound 35b . ¹ H NMR (400MHz, CDCl ₃ )δ 7.33(d, J =16.6Hz, 1H), 7.04(s, 2H), 5.85(d, J =16.6Hz, 1H), 2.67(q, J =7.6Hz, 4H), 1.38(s, 12H), 1.20(t, J =7.6Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07min (LCMS method 2).

Step 3: Synthesis of ( E )-3-(4-(4-amine-2-chloroquinazolin-8-yl)-3,5-diethylphenyl)acrylonitrile (( E )-3-(4 -(4-amino-2-chloroquinazolin-8-yl)-3,5-diethylphenyl)acrylonitrile) (compound 35c)

8-Bromo-2-chloroquinazolin-4-amine (90mg, 0.35mmol, Ark Pharm Inc, AK-28702), compound 35b (130mg, 0.42mmol), tripotassium phosphate (96mg, 0.45mmol) and 1, A mixture of 1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (23 mg, 0.04 mmol) was dissolved in a mixture of N , N -dimethylformamide:water (80 under argon) : 20,5mL). The reaction was heated at 80°C for 60 minutes. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane was added and the mixture was filtered through a 2 cm layer of silica gel washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the residue was treated with hexanes in a sonic bath. The solid product was filtered off and washed twice with hexanes to provide the title compound 35c . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.39 (bs, 2H), 8.29 (dd, J =7.2, 2.5Hz, 1H), 7.67 (d, J =16.7Hz, 1H), 7.61-7.54 (m ,2H),7.46(s,2H),6.52(d, J =16.7Hz,1H),2.22-2.01(m,4H),0.91(t, J =7.5Hz,6H).LCMS(m/z) 363.3 [M+H], Tr=2.68 min (LCMS method 2).

Step 3: Synthesis of ( E )-4-((4-amine-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amine) Benzonitrile (Compound 35)

Compound 35c (40 mg, 0.11 mmol), 4-cyanoaniline (18 mg, 0.154 mmol, Sigma-Aldrich) and N -methyl-2-pyrrolidinone (1 mL) on dry in 1,4-dioxane ( A mixture of hydrogen chloride solution in 4M, 3 μL, 0.011 mmol) was heated at 120° C. for 12 hours. The reaction mixture was cooled to room temperature and purified directly by HPLC reverse phase chromatography (0 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford compound 35 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 10.57-9.84(m,1H), 9.82-8.84(m,2H), 8.27(bs,1H), 7.86-7.22(m,7H), 6.62(d, J =16.8Hz,1H),2.40-1.98(m,4H),0.94(t, J =7.2Hz,6H).LCMS(m/z)445.4[M+H],Tr=2.59min(LCMS method 2 )

Example 36

( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amine)nicotinecarbonitrile (( E )-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile)-compound 36

Synthesis of ( E )-6-((4-amine-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amine)nicotine methyl Nitrile (Compound 36)

Compound 35c (40 mg, 0.11 mmol), 6-amine nicotine carbonitrile (53 mg, 0.44 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (28 mg, 0.22 mmol) and [ (2-bis-cyclohexylphosphino-3,6-dimethoxy-2 ' ,4 ' , 6' -triisopropyl-1,1' - diphenyl)-2-(2' - amine -1,1' - diphenyl)]palladium(II) mesylate ([(2-di-cyclohexylphosphino-3,6-dimethoxy-2 ' ,4 ' ,6' - triisopropyl - 1,1'- biphenyl)-2-(2' - amino-1,1' - biphenyl)]palladium(II)methanesulfonate) (9 mg, 0.011 mmol) in N-methyl-2-pyrrolidone (1 mL) under argon combine. The reaction was heated in a sealed vessel at 120°C for 4 hours. The reaction mixture was cooled to room temperature and then directly purified by HPLC reverse phase chromatography (gradient from 0 to 100% acetonitrile in water with 0.1% trifluoroacetic acid) to provide the title compound 36 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ )δ 13.54(bs,1H), 12.09(bs,1H), 9.62(bs,1H), 9.38(bs,1H), 8.46(d, J =8.2Hz,1H ),8.37-8.15(m,1H),7.94-7.83(m,2H),7.80-7.66(m,3H),7.56-7.27(m,2H),6.76(d, J =16.7Hz,1H), 2.40-2.01 (m, 4H), 0.94 (t, J = 7.5 Hz, 6H). LCMS (m/z) 446.4 [M+H], Tr = 1.98 min (LCMS method 2).

Example 37

( E )-1-(2-((4-cyanophenyl)amine)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazoline-4 -yl) urea (( E )-1-(2-((4-Cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea)-compound 37

Synthesis of ( E )-1-(2-((4-cyanophenyl)amine)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazoline- 4-yl) urea (compound 37)

Compound 2 (42 mg, 0.10 mmol) was suspended in dry dichloromethane (2 mL) and phosgene (phosgene) was added dropwise after the addition of N,N-diisopropylethylamine (0.1 mL, 0.57 mmol). 0.5 mL, 20% solution in toluene). The mixture was stirred at 50°C for 1 hour. Another portion of N,N -diisopropylethylamine (0.1 mL, 0.57 mmol) and phosgene (0.2 mL, 20% solution in toluene) were added to the reaction mixture and stirred at 50 °C for an additional hour. The mixture was cooled to room temperature and saturated aqueous ammonia solution (1 mL) was added. The volatiles were removed under reduced pressure and the crude residue was purified by HPLC (HPLC prep column Phenomenex Gemini 10u, C18, 250 x 21.2 mm, 10 mL/min) using a gradient from 50 to 100% acetonitrile in water to provide the title compound 37 . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.35(bs, 1H), 8.26-8.07(m, 1H), 7.78-7.65(m, 3H), 7.62-7.45(m, 3H), 7.44-7.30( m,3H),7.29-7.16(m,3H),6.43(d, J =16.7Hz,1H),1.81(s,6H).LCMS(m/z)460.3[M+H],Tr=3.98min (LCMS Method 1).

Example 38

( E )-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl ) amine) benzonitrile (( E )-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino )benzonitrile)-Compound 38

Step 1: Synthesis of 4-bromo-3,5-dimethylbenzoic acid (compound 38a)

4-Bromo-3,5-dimethylbenzonitrile (4-Bromo-3,5-dimethylbenzonitrile) (630 mg, 3 mmol, Ark Pharm Inc, AK-44760) was dissolved in ethanol (1 mL) and 8M hydrogen was added sodium oxide solution (5 mL) and the reaction mixture was stirred at 120°C in a sealed vessel for 12 hours. The reaction mixture was diluted with water (100 mL) and washed with ether (2 x 50 mL), the aqueous layer was acidified with concentrated hydrochloric acid (to pH=3) and extracted with ether (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide the title compound 38a . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.72 (s, 2H), 2.41 (s, 6H).

Step 2: Synthesis of 1-(4-bromo-3,5-dimethylphenyl)ethanone (Compound 38b)

Compound 38a (100 mg, 0.44 mmol) was suspended in dry 1,4-dioxane (5 mL) and methyllithium (0.8 mL, 1.6 M solution in ether) was added dropwise under argon. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of ethanol (10 mL) and concentrated under reduced pressure. The solid residue was extracted with ethyl acetate (3 x 10 mL). The combined organic solutions were concentrated under reduced pressure to provide the title compound 38b . LCMS (m/z) 227.0 [M+H], Tr=4.65 min (LCMS method 1).

Step 3: Synthesis of ( E )-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrile (( E )-3-(4-bromo-3,5-dimethylphenyl)but -2-enenitrile) and ( Z )-3-(4-bromo-3,5-dimethyl Phenyl)but-2-enenitrile (( Z )-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrile) (Compound 38c and Compound 38d)

Compound 38b (95 mg, 0.42 mmol) and diethyl(cyanomethyl)phosphonate (70 μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated under reduced pressure at 30 °C. The resulting solid was allowed to stand at room temperature for 4 hours. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using a gradient from 0 to 10% ethyl acetate in isohexane to afford the title compound 38c LCMS (m/z) 250.0 [M+H], Tr= 5.01 min (LCMS method 1); and title compound 38d LCMS (m/z) 250.0 [M+H], Tr=4.48 min (LCMS method 1).

Step 4: Synthesis of ( E )-4-((4-amine-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazoline -2-yl)amine)benzonitrile (compound 38)

Compound 32a (20 mg, 0.047 mmol), compound 38c (20 mg, 0.080 mmol) and bis(tri-tert-butylphosphino)palladium(0) (20 mg) in N,N -dimethylformamide (2 mL) , 0.039 mmol) was heated at 100 °C for 14 hours under argon. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then HPLC (preparative grade column Phenomenex Gemini 10micron C18, 250 x 21.2 mm, 10 mL) /min, repurification on a gradient from 10 to 100% acetonitrile in water) to provide the title compound 38 . ¹ H NMR (600MHz, DMSO- d ₆ ) δ 8.23 (bs, 1H), 7.83-7.72 (m, 2H), 7.60-7.29 (m, 7H), 6.17 (q, J = 1.0Hz, 1H), 2.52 -2.51 (m, 3H), 1.96 (s, 6H). LCMS (m/z) 430.9 [M+H], Tr=3.83 min (LCMS method 1).

Example 39

( Z )-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl ) amine) benzonitrile (( Z )-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino )benzonitrile)-compound 39

Synthesis of ( Z )-4-((4-amine-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazoline-2- yl)amine)benzonitrile (compound 39)

Compound 32a (20 mg, 0.047 mmol), compound 38d (18 mg, 0.072 mmol) and bis(tri-tert-butylphosphino)palladium(0) (20 mg) in N,N -dimethylformamide (2 mL) , 0.039 mmol) was heated at 100 °C for 14 hours under argon. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then HPLC (preparative grade column Phenomenex Gemini 10micron C18, 250 x 21.2 mm, 10 mL) /min, repurification on a gradient from 10 to 100% acetonitrile in water) to provide the title compound 38 . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.22 (bs, 1H), 7.84-7.71 (m, 4H), 7.62-7.29 (m, 5H), 5.89-5.79 (m, 1H), 2.36 (d, J = 1.5 Hz, 3H), 1.97 (s, 6H). LCMS (m/z) 430.9 [M+H], Tr = 3.76 min (LCMS method 1).

Example 40

4-((4-Amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amine)benzyl Nitrile (4-((4-Amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile)-compound 40 (mixture E / Z = 1/1)

及

(混合物)

and

(mixture)

Step 1: Synthesis of 4-bromo-3,5-dimethylbenzaldehyde (Compound 40a)

A mixture of 4-bromo-3,5-dimethylbenzonitrile (2 g, 9.57 mmol, Ark Pharm Inc, AK-44760) in dichloromethane (25 mL) was cooled to -62 °C. A solution of diisobutylaluminium hydride (in 1M dichloromethane, 11 mL) was added dropwise and the reaction left to reach room temperature within 2 hours. After that, 5% aqueous hydrochloric acid (10 mL) was added and the reaction mixture was heated to reflux for 30 minutes. Next, the reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried with calcium chloride. The solvent was removed under reduced pressure and the crude product was treated by silica gel chromatography (gradient from 0 to 10% ethyl acetate in isohexane) to provide the title compound 40a . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 7.57 (s, 2H), 2.50 (s, 6H). HRMS: Calculated (ESI+) for C ₉ H ₁₀ BrO [M+H] 212.9915 , the measured value is 212.9913. LCMS (m/z) 213.0 [M+H], Tr=4.59 min (LCMS method 1).

Step 2: Synthesis of 3-(4-bromo-3,5-dimethylphenyl)-2-methacrylonitrile (3-(4-bromo-3,5-dimethylphenyl)-2-methylacrylonitrile) (Compound 40b ) mixture E / Z = 1/1

Compound 40a (100 mg, 0.47 mmol) and diethyl(1-cyanoethyl)phosphonate (70 μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated under reduced pressure at 30 °C. The resulting solid was allowed to stand at room temperature for 4 hours. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using a gradient from 0 to 10% ethyl acetate in isohexane to provide the title compound 40b as a 1 : 1 mixture of E/Z isomers. LCMS (m/z) 250.0 [M+H], Tr=5.07 and 5.10 min (LCMS method 1).

Step 4: Synthesis of 4-((4-amine-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl ) amine) benzonitrile (compound 40) mixture E / Z = 1/1

Compound 32a (20 mg, 0.047 mmol), compound 40b (20 mg, 0.080 mmol) and bis(tritert-butylphosphino)palladium(0) (20 mg) in N,N -dimethylformamide (2 mL) , 0.039 mmol) was heated at 100 °C for 8 hours under argon. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 50 to 100% ethyl acetate in isohexane) and then HPLC (preparative grade column Phenomenex Gemini 10micron C18, 250 x 21.2 mm, 10 mL) /min, gradient from 10 to 100% acetonitrile in water) to provide the title compound 40 as a 1:1 mixture of E/Z isomers. ¹ H NMR (600MHz, DMSO- d ₆ )δ 8.26(s, 1H), 7.82-7.74(m, 2H), 7.64-7.23(m, 7H), 2.23-2.19(m, 3H), 1.96(s, 6H). LCMS (m/z) 430.8 [M+H], Tr=3.86 min (LCMS method 1).

Example 41

( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-2- ( E )-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile )-Compound 41

Step 1: Synthesis of 4-((8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)amine)benzonitrile (4-((8-bromo-4-oxo-3, 4-dihydroquinazolin-2-yl)amino)benzonitrile) (compound 41a)

A mixture of compound 34a (260 mg, 1 mmol) and 4-aminobenzonitrile (130 mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 130 °C for 30 min. The reaction mixture was cooled to room temperature and ether (10 mL) was added. The solid product was filtered off and washed with diethyl ether (3 x 20 mL) to provide the title compound 41a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 11.13(bs,1H), 9.41(bs,1H), 8.11(d, J =8.8Hz,2H), 8.04-7.96(m,2H), 7.80(d , J =8.8Hz,2H),7.19(t, J =7.8Hz,1H).HRMS: The calculated (ESI+) of C ₁₅ H ₁₀ ON ₄ Br[M+H] is 341.0033, and the measured value is 341.0033. LCMS (m/z) 341.1 [M+H], Tr 4.52 min (LCMS method 1).

Step 2: Synthesis of ( E )-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo- 3,4-Dihydroquinazolin-2-yl)amine)benzonitrile (Compound 41)

Compound 41a (68 mg, 0.2 mmol), compound 1c (85 mg, 0.3 mmol), tripotassium phosphate (92 mg, 0.4 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloride A mixture of palladium (26 mg, 0.04 mmol) was dissolved in a mixture of N , N -dimethylformamide:water (85:15, 40 mL) under argon. The reaction was heated to 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (gradient from 50 to 80% ethyl acetate in isohexane) and then by HPLC reverse phase chromatography (gradient from 5 to 100% of ethyl acetate). (acetonitrile in water with 0.1% trifluoroacetic acid) was repurified to provide the title compound 41 as the TFA salt. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.96 (bs, 1H), 9.15 (bs, 1H), 8.05 (dd, J =7.9, 1.6Hz, 1H), 7.75 (d, J =16.7Hz, 1H) ), 7.57(dd, J =7.3, 1.6Hz, 1H), 7.53(s, 2H), 7.48-7.29(m, 6H), 6.56(d, J =16.7Hz, 1H), 1.93(s, 6H) .LCMS (m/z) 418.3 [M+H], Tr=2.72 min (LCMS method 2).

Example 42

Alternative Synthesis of ( E )-3-(4-Bromo-3,5-dimethylphenyl)acrylonitrile - Compound 1b

Alternative synthesis of ( E )-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (Compound 1b)

Potassium tert-butoxide (168 mg, 1.5 mmol) was added with stirring to a solution of diethylcyanomethylphosphonate (266 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0 °C. After that, compound 40a (212 mg, 1 mmol) in tetrahydrofuran (10 mL) was dropped into the reaction mixture at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water. Ethyl acetate was added and the organic layer was washed with brine, dried over anhydrous calcium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient from 0 to 20% ethyl acetate in isohexane) to provide the title compound lb. ¹ H NMR (400MHz, CDCl ₃ )δ 7.25(d, J =16.6Hz, 1H), 7.12(s, 2H), 5.84(d, J =16.6Hz, 1H), 2.42(s, 6H).LCMS( m/z) No MS signal, Tr=2.78min (LCMS method 2).

Example 43

Alternative Synthesis of 4-((4-Amino-8-bromoquinazolin-2-yl)amine)benzonitrile - Compound 8a

Step 1: Synthesis of 3-bromo-2-((triphenylphosphoranylidene)amine)benzonitrile (3-bromo-2-((triphenylphosphoranylidene)amino)benzonitrile) (compound 43a)

A solution of triphenylphosphine (10.65 g, 40.6 mmol) in dichlormomethane (200 mL) was slowly treated with bromine (6.49 g, 40.6 mmol) at 0 °C for 5 min. Triethylamine (8.22 g, 81.2 mmol) was added followed by 2-amino-3-bromobenzonitrile (4.00 g, 20.3 mmol, Abblis, AB1000095). Next, the ice bath was removed and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted twice with dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was treated with silica gel chromatography (gradient from 0 to 30% ethyl acetate in isohexane) to provide the title compound 43a . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80-7.70 (m, 6H), 7.66 (dt, J = 7.9, 1.4 Hz, 1H), 7.64-7.58 (m, 3H), 7.57-7.47 (m, 6H),7.40(dt, J =7.7,1.5Hz,1H),6.64(td, J =7.8,1.5Hz,1H).LCMS(m/z)457.1[M+H],Tr=2.99min(LCMS Method 2).

Step 2: Alternative synthesis of 4-((4-amine-8-bromoquinazolin-2-yl)amine)benzonitrile (compound 8a)

Benzonitrile (173 mg, 1.20 mmol, Sigma-Aldrich) was added to a solution of compound 43a (500 mg, 1.09 mmol) in 2-methyltetrahydrofuran (10 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min . 2M ammonia in isopropanol (3.3 mL, 6.6 mmol) was added and the reaction mixture was heated to reflux for 3 hours then concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0 to 40% ethyl acetate in isohexane) to provide the title compound 8a . ¹ H NMR (400MHz, DMSO- d ₆ )δ 9.74(s, 1H), 8.35(d, J =8.8Hz, 2H), 8.16(d, J =8.0Hz, 1H), 8.01(d, J =7.5 Hz,1H),7.71(d, J =8.8Hz,2H),7.16(t, J =7.8Hz,1H).LCMS(m/z)340.0[M+H],Tr=4.06min (LCMS method 1 ).

biological example

Instance A

High-throughput screening of anti-HIV-1 RT (reverse transcriptase)

Compounds were screened in a miniaturized high-throughput cytopathic effect assay for activity against HIV-1 HBX2 (wild type) and HIV-1 reverse transcriptase mutants K103N and Y181C. In Tables 1 and 2 below, "w.t." means the results of the test compound performed with wild type 1 and "w.t. assay 2 (w.t. assay 2)" means performed with the wild type on the same day that the mutant was tested for the compound Results for tested compounds. Therefore, "w.t. Trial 2" is The test was performed under the same conditions as the mutant test compound and provides a direct comparison of the test to the mutant.

Ten-point serial dilutions of compounds were generated in DMSO in natural log-half steps. AZT (5 μM) line was used as positive control and DMSO line was used as negative control. An echo-acoustic dispenser was used to deliver 200 mL of sequentially diluted compounds into sterile 384-well tissue culture assay dishes. Two million MT-4 cells were incubated with each of the three viruses at an MOI of 0.0005 at 37°C in separate 1 mL infection tubes. Cells were diluted to 50,000 cells/mL in cell culture medium (RPMI + 10% FBS). Infected cells were added to 384-well assay plates containing sequentially diluted compounds. The assay plates were incubated for 5 days in a humidified incubator set at 37°C and 5% CO ₂ . To measure HIV cytopathic effects, 40 [mu]L of Cell TiterGlo was added to each well and the resulting fluorescent signal was read with an Envision disc reader (Perkin Elmer). Data were normalized to positive and negative controls in each disk and expressed in % CPE Protection. The _EC50 value was defined as the concentration of compound that caused a 50% reduction in fluorescence signal and was calculated by nonlinear regression using the Pipeline Pilot software using a four-parameter fit equation (Accelrys, San Diego, CA). The results are disclosed in Table 1.

High-throughput screening was also performed on verapine (NPV), lipivirine (RPV) and efavirenz (EFV). Virapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #N391275). Lipivering was obtained from Key Organics Ltd. (Camelford, Cornwall, United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #E425000). The results are shown in Table 2 below.

* w.t.試驗2與用K103N及Y181C突變體的試驗同天執行。ND：未測定的

*wt Experiment 2 was performed on the same day as the experiments with K103N and Y181C mutants. ND: Not determined

It is to be understood that the EC ₅₀ can be assessed using techniques known in the relevant art. In a certain embodiment, the compound exhibits less than about 3000 nM in wild type or any HIV RT mutant when measured by the method disclosed in the aforementioned "High-throughput Screening of HIV Mutants K103N and Y181C" experimental section _EC50 . In a certain embodiment, the compound exhibits less than about 1000 nM, 500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM or _EC50 of 1 nM.

Example B

Tolerance status to HIV-1 RT (reverse transcriptase) mutants

Compounds were tested for antiviral activity against a panel of anti-NNRTI viruses. A panel of 8 asexual site-directed mutagenic viruses representing the major pathways of resistance development to ripivilene (RPV), efavirenz (EFV), and verapine (NVP) using HIV-1 reverse transcriptase containing both Single and double mutations. Further details and background can be found in Janssen et al, J. Med. Chem, 2005, 48, 1901-1909; Das et al., Proc. Nat. Acad. Sci., 2008, vol., 105, no. 5, 1466-1471; and Kuroda et al., Nature Chemistry, 2013, DOI: 10.1038/NCHEM.1559. Retention of sufficient antiviral ability to the wild-type-related K103N mutation was considered particularly desirable when this mutation was present in a minority (1.4%) of treatment-naïve patients. The HIV-1 recombinants encoding the reverse transcriptase mutations K103N, Y181C, Y188L, G190A, K103N/Y181C, L100I/Y181C, E138K or E138K/M184V were constructed by site-directed mutagenesis. Wild-type and mutant virus lines were prepared by transfecting an infectious proviral HXB2-line cDNA clone into MT-2 cells and obtaining the cell supernatant. Wild-type and mutant HIV-1 clones were infected with MT-2 cells at a multiplicity of infection (MOI) of 0.005 by gentle mixing for 3 hours at 37°C, followed by cell culture in 50 μL of complete RPMI per well. media (containing 10% fetal bovine serum (FBS) and 10% penicillin-streptomycin) at a density of 16,667 cells to three serial dilutions containing 50 μL in RPMI media 96-well plates for test compounds. After 5 days of incubation in the presence of 5% _CO in a 37°C humidified incubator, 100 μL of Cell TiterGlo reagent (Promega Biosciences, Inc., Madison, WI) was added to each well and the relative relative was measured with an Envision disc reader. Light units (relative light units, RLU). Virus-induced cytopathies were determined as percentages by subtracting the signal from the untreated control group from the RLU measurements of samples that sufficiently inhibited viral replication. The _EC50 value was defined as the concentration of compound that caused a 50% reduction in viral replication. Data analysis of observed antiviral activity in MT-2 cells was performed using XL-fit ^™ software to calculate _EC50 from an 8-point dose-response curve using the following equation:

where y =viral inhibition, x =drug concentration, M =maximum inhibition, H=minimum inhibition and n=Hill coefficient. _EC50 values (mean ± standard deviation) were calculated from at least three independent experiments performed in triplicate. Tolerance ratings were calculated as the ratio of the mean _EC50 for each mutant/wild-type virus. The results are disclosed in Figure 1 and in Tables 3 and 4 below.

ND：未測定

ND: Not determined

Tolerance status to HIV-1 RT mutants was also performed with verapine (NPV), lipivirine (RPV) and efavirenz (EFV). Virapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #N391275). Lipivering was obtained from Key Organics Ltd. (Camelford, Cornwall, United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #E425000). The results are shown in Table 4 below.

ND：未測定

ND: Not determined

Example C

hERG test

cell:

AVIVA's CHO cell line, which stably displays hERG channels, was used for the study. Cells were cultured in DMEM/F12 containing 10% FBS, 1% penicillin/streptomycin and 500 μg/ml G418. Before testing, use Accumax (Innovative Cell Technologies) to obtain cells.

Solution:

For electrophysiological recordings, the following solutions were used:

External solution: 2 mM CaCl2; 2 mM MgCl2; 4 mM KCl; 150 mM NaCl; 10 mM Glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5M NaOH).

Internal solution: 140 mM KCl; 10 mM MgCl2; 6 mM EGTA; 5 mM HEPES-Na; 5 mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1 M KOH).

Electrophysiology:

All cellular recordings were performed using a PX 7000A (Axon Instruments) with AVIVA's SealChip ^™ technology. Cells were voltage limited to a holding potential of -80 mV. The hERG current was then activated to -50 mV for 300 ms by a depolarization step. The first step at -50mV was used as a baseline for measuring the peak amplitude of the tail current. Next, the voltage was increased to +20 mV for 5 seconds to activate the channel. Finally, return to -50mV for 5 seconds to remove activation and record the deactivation tail current.

Test object manipulation and dilution:

All items were prepared from 10 mM DMSO stocks. Mix vigorously by sonicating for 20 minutes after mixing. Compounds were diluted to test concentrations in glass vials using external solutions prior to testing. Dilutions should not be prepared more than 20 minutes before use.

Electrophysiology Program

After reaching full cell configuration, cells were monitored for 90 seconds to assess stability and then washed with external solution for 66 seconds. The voltage condition is then applied to the thin cell every 12 seconds throughout the program cell. Only stable cells with recorded parameters above the threshold were admitted to the drug addition procedure.

An external solution containing 0.1% DMSO (vehicle) was applied to the cells to establish a baseline. After being allowed to stabilize with the current for 3 to 10 minutes, the test article was used. The test article solution was added to the cells in 4 separate additions. The cells were maintained in the test solution until the effect of the test article reached steady state, up to 12 minutes. Next, 1 μM cisapride (positive control) was added. Finally, wash out the external solution until the recovery current reaches steady state.

data analysis

Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments) and Origin (OriginLab Corporation) software. The results are disclosed in Table 5. The larger value in Table 5 represents the maximum achievable concentration in the test (eg, the compound that reaches its solubility limit).

The hERG test was also performed on ripivilene (RPV). The result was 0.5 μM.

The particular pharmacological response observed may vary depending on and depending on the particular active compound or the presence or absence of the pharmaceutical carrier selected, as well as the type of formulation and mode of administration used, and such expected variation or difference in results is based on The practice of this disclosure is carefully considered.

The examples disclosed herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It is to be understood that the individual steps described herein may be combined. It is also understood that separate batches of compounds can be combined and subsequently used in subsequent synthetic steps.

All references, including publications, patents, and patent documents, are incorporated herein by reference as if individually incorporated by reference. This disclosure provides sources of various implementations and techniques. It is to be understood, however, that many changes and modifications can be made while remaining within the spirit and scope of the present disclosure.

Claims (16)

A pharmaceutical composition comprising a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof:

where Q is

or

; X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), but at most two of X ¹ , X ² and X ³ are N; R ¹ is -H, -CN, - OR ^a , halogen or C _1-6 alkyl; R ² is -H, -CN, -OR ^a or C _1-6 alkyl; R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁴ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁵ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 Alkyl; R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁷ is C _1-6 alkyl, halogen, -OR ^a , -CN or -NO ₂ ; R ⁸ is C _1-6 alkyl, halogen, -OR ^a , -CN or -NO ₂ ; R ⁹ is -H or C _1-6 alkyl; R ¹⁰ is -H or C _1-6 alkyl; each R ¹¹ is independently -H, -CN, -OR ^a , halogen or C _1-6 alkyl; each R ^a and R ^b are independently -H, C _1-6 alkyl or C _3-10 cycloalkyl; and one, two, three or four additional therapeutic agents independently selected from raltegravir, Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), maveroc, envoviride, Epzicom® (Livexa®, abacavir sulfate + lamevudine) , ABC+3TC), Trizivir® (Abacavir Sulfate+Civudine+Lamevudine, ABC+AZT+3TC), Antifovir, Antifovir Disoproxil, Stribild® (Etige Wei + cobicita + tenofovir disoproxil fumarate + emtricitabine), rilpivirine, rilpivirine hydrochloride (rilpivirine hydrochloride), Complera® (Eviplera®, rilpivirine hydrochloride) Virin + tenofovir disoproxil fumarate + emtricitabine), cobicita, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine) , Antanavir, Antanavir Sulfate, Dotegravir, Elvitegravir, Aluvia® (Kaletra®, Ropinavir + Retonavir), Retonavir, Emtricitabine, Sulfate Antanavir + Retonavir, Darunavir, Lamevudine, Plastine, Fosapenavir, Fosapenavir Calcium, Efavirenz, Combivir® (Chifodine + Lamev Ding, AZT+3TC), azovirine, fenavir, fenavir mesylate, interferon, didanole letter, staphudine, indinavir, indinavir sulfate, tenofovir + lamevudine, chiffudine, verapine, saquinavir, saquinavir mesylate, adipate Interleukin, Dideoxycytidine, Tipnavir, Amperavir, Deravidine, Deravidine Mesylate, Radha-108 (Receptol), Hlviral, Lamevudine + Tenofo Fumarate Viridin, efavirenz + lamevudine + tenofovir disoproxil fumarate, phosphine azide, lamevudine + verapine + chifeudine, abacavir, abaca sulfate Wei, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide (tenofovir alafenamide), tenofovir alafenamide fumarate Tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. The pharmaceutical composition of claim 1, wherein Q is

The pharmaceutical composition of claim 1, wherein X ¹ , X ² and X ³ are each CH. The pharmaceutical composition of claim 1, wherein X ¹ , X ² and X ³ are C(R ¹¹ ); each R ¹¹ is independently selected from -H, -CN, -OR ^a , halogen and C _1-6 alkane and R ¹ is selected from -H, -CN, -OR ^a , halogen and C _1-6 alkyl. The pharmaceutical composition of claim 1, wherein R ³ is -NH ₂ or -OH. The pharmaceutical composition of claim ¹ , wherein R4 is H, and R5 is -H, ^-ORa , halogen, _-NO2 , -CN, ^-NRaRb , ^{-NHC (} O ^{) NRaRb} or C _1-6 alkyl. The pharmaceutical composition of claim 1, wherein R ⁴ , R ⁵ and R ⁶ are -H. The pharmaceutical composition of claim 1, wherein R ⁷ is C _1-6 alkyl. The pharmaceutical composition of claim 1, wherein R ⁸ is C _1-6 alkyl. The pharmaceutical composition of claim 1, wherein R ⁷ and R ⁸ are C _1-6 alkyl. The pharmaceutical composition of claim 1, wherein R ⁷ and R ⁸ are methyl groups. The pharmaceutical composition of claim 1, wherein Q is

The pharmaceutical composition of claim 1, wherein the compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

or its tautomer or its pharmaceutically acceptable salt. The pharmaceutical composition of any one of claims 1 to 13, wherein one of the additional therapeutic agents is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate ( tenofovir alafenamide fumarate) and tenofovir alafenamide hemifumarate. Use of a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of HIV infection,

where Q is

or

; X ¹ , X ² and X ³ are each independently N or C(R ¹¹ ), but at most two of X ¹ , X ² and X ³ are N; R ¹ is -H, -CN, -OR ^a , halogen or C _1-6 alkyl; R ² is -H, -CN, -OR ^a or C _1-6 alkyl; R ³ is -H, -OR ^a , -NR ^a R ^b , - NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁴ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁵ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkane base; R ⁶ is -H, -OR ^a , halogen, -NO ₂ , -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C _1-6 alkyl; R ⁷ is C _1-6 alkyl, halogen, -OR ^a , -CN or -NO ₂ ; R ⁸ is C _1-6 alkyl, halogen, -OR ^a , -CN or -NO ₂ ; R ⁹ is -H or C _1-6 alkyl; R ¹⁰ is -H or C _1-6 alkyl; each R ¹¹ is independently -H, -CN, -OR ^a , halogen or C _1-6 alkyl; each R ^a and R is independently ^-H , C _1-6 alkyl or C _3-10 cycloalkyl; wherein the drug further comprises one, two, three or four additional therapeutic agents or is combined with one, two, three or four A combination of additional therapeutic agents, the one, two, three or four additional therapeutic agents are independently selected from raltegravir, Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), Maveroc, Envoviride, Epzicom® (Livexa®, Abacavir Sulfate + Lamevudine, ABC+3TC), Trizivir® (Abacavir Sulfate + Chivudine + Lamevudine) , ABC+AZT+3TC), Antifovir, Antifovir disoproxil, Stribild® (elvitegravir + cobicita + tenofovir disoproxil fumarate + emtricita pyridine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine + tenofovir disoproxil fumarate + emtricitabine), Bicecitabine, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), antanavir, antanavir sulfate, dotegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir + ritonavir), ritonavir, emtricitabine, antanavir sulfate + ritonavir, darunavir, lamevudine, boras tincine, frasapenavir, fosapenavir calcium, efavirenz, Combivir® (chifodine + la medvudine, AZT+3TC), azovirine, fenavir, fenavir mesylate, interferon, didanosin, stavedine, indinavir, indinavir sulfate, Tenofovir + lamevudine, chivudine, verapine, saquinavir, saquinavir mesylate, aldesleukin, dideoxycytidine, tipnavir, amperavir, Ravidine, deravirdine mesylate, Radha-108 (Receptol), Hlviral, lamevudine + tenofovir disoproxil fumarate, efavirenz + lamevudine + fumarate Nofovir disoproxil, phosphine azide, lamevudine + verapine + chiffudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, fumarate Tenofovir disoproxil, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate Tenofovir alafenamide hemifumarate. The use of claim 15, wherein one of the additional therapeutic agents is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and hemifumarate Tenofovir alafenamide hemifumarate.

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